US 2012O190743A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0190743 A1 Bain et al. (43) Pub. Date: Jul. 26, 2012

(54) COMPOUNDS FOR TREATING DISORDERS Publication Classification OR DISEASES ASSOCATED WITH (51) Int. Cl NEUROKININ 2 RECEPTORACTIVITY A6II 3L/23 (2006.01) (75) Inventors: Jerald Bain, Toronto (CA); Joel CD7C 69/30 (2006.01) Sadavoy, Toronto (CA); Hao Chen, 39t. ii; C Columbia, MD (US); Xiaoyu Shen, ( .01) Columbia, MD (US) A6IPI/00 (2006.01) s A6IP 29/00 (2006.01) (73) Assignee: UNITED PARAGON A6IP II/00 (2006.01) ASSOCIATES INC., Guelph, ON A6IPI3/10 (2006.01) (CA) A6IP 5/00 (2006.01) A6IP 25/00 (2006.01) (21) Appl. No.: 13/394,067 A6IP 25/30 (2006.01) A6IP5/00 (2006.01) (22) PCT Filed: Sep. 7, 2010 A6IP3/00 (2006.01) CI2N 5/071 (2010.01) (86). PCT No.: PCT/US 10/48OO6 CD7C 69/33 (2006.01) S371 (c)(1) (52) U.S. Cl...... 514/552; 554/227; 435/375 (2), (4) Date: Apr. 12, 2012 (57) ABSTRACT Related U.S. Application Data Compounds, pharmaceutical compositions and methods of (60) Provisional application No. 61/240,014, filed on Sep. treating a disorder or disease associated with neurokinin 2 4, 2009. (NK) receptor activity. Patent Application Publication Jul. 26, 2012 Sheet 1 of 12 US 2012/O190743 A1

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COMPOUNDS FORTREATING DSORDERS plex interplay of etiological factors including the role of OR DISEASES ASSOCATED WITH second messengers mediating membrane bound and intrac NEUROKININ 2 RECEPTOR ACTIVITY ellular processes. This has led to investigation of hormonal pathways Such as the hypothalamic-pituitary-adrenal (HPA) CROSS-REFERENCE TO RELATED axis (the activity of which is elevated in 20-40% of commu APPLICATIONS nity-dwelling patients with major depressive disorder), thy 0001. This application claims the benefit of U.S. Provi roid axis (5-10% of patients evaluated with major depressive sional Application No. 61/240,014, filed Sep. 4, 2009, which disorder have previously undetected thyroid dysfunction), is hereby incorporated by reference. growth hormone, prolactin, testosterone and the role of inflammatory processes and their markers such as interleu FIELD OF THE INVENTION kin-1 and -6 and tumour necrosis factor. 0002 The invention relates to compounds, pharmaceuti 0008 Most people with major depressive disorder experi cal compositions and methods for treating disorders or dis ence some degree of symptom return, and 20-30% exhibit a eases associated with neurokinin 2 (NK) receptor activity. chronic course (defined as a syndromal level of depressive symptom severity for two years or more (Treatment of BACKGROUND OF THE INVENTION Chronic Depression (Editorial))). Depressive Mood Disorders 0009 All depressed people require continuation of phar macotherapy to permit recovery and prevent relapse. A Sub 0003. Depressive mood disorders are a group of mood stantial proportion of depressed patients require maintenance disorders characterized by feelings of depression. Depressive pharmacotherapy to prevent recurrence and further consoli mood disorders include major depressive disorder, dysthymic date psychosocial recovery. However, while one of the major disorder, depressive phase of bipolar disorder, depression due factors in effective antidepressant therapy is maintaining the to a general medical condition Such as depression associated patient on an adequate dose of medication for an adequate with dementia or schizoaffective disorder, substance-induced depression, postpartum depression and seasonal affective dis duration, this is often difficult. Many patients fear taking order. current antidepressants because of real or imagined physical 0004 Major depressive disorder (also known as major effects. Some patients prefer to use so-called natural health depression, clinical depression, unipolar depression and uni promoting Substances and non-pharmacological interven polar disorder) is very prevalent in the general population. tions. Patients who are prepared to take antidepressants often Recent North American data show a 14.5% lifetime risk of encounter a wide array of side effects, which leads them to be major depression in adults and 8.1% one year prevalence non-compliant or to reject therapy entirely. Selective seroto (Results from the 2004 National Survey on Drug Use and nin reuptake inhibitors (SSRI) for example, commonly Health: National findings: Revisions as of Sep. 8, 2005; induce gastrointestinal upset, headaches, sleep disturbance Department of Health and Human Services. Substance Abuse and significant sexual impairments among many other side and Mental Health Services Administration Office of Applied effects. Most antidepressants have at least some significant Studies). side effects and these limit clinicians capacity to effectively 0005. The mean duration of a depressive episode with treat many patients. modern treatments is about 16 weeks, although some data 0010 Major depressive disorder can be associated with Suggest alonger duration of about 6-8 months, far less than in other disorders and/or syndromes, including disorders of the the pre-antidepressant therapy era when the duration was brain or nervous system, anxiety disorder (which includes about 18 months (Kendler, McLeod, Patten). generalized anxiety disorder, panic disorder, phobias, obses 0006 Antidepressants have had some impact on the treat sive-compulsive disorder, post-traumatic stress disorder, ment of major depressive disorder and on reducing the Suf separation anxiety, social anxiety disorder, otherwise known fering of patients. Not all of the impact has been positive. as Social phobia, bipolar disorder, and dementia); sexual dys Patients with major depressive disorder are often impaired in function; Substance abuse, eating disorders and hormone dis function and frequently have co-morbid disorders such as orders, such as thyroid dysfunction, hypogonadism, meno Substance abuse that can be attributed to the underlying major depressive disorder. Major depressive disorder leads to pause, etc. Treatment of the major depressive disorder often increased utilization of health services and can have a devas leads to improvement in these related disorders and Syn tating impact on Social structure and Societal economics. dromes. 0007. The cause of major depressive disorder is not fully 0011. In addition, some therapeutic agents used to treat known. Disturbance of monoamine synthesis and activity has depression are also effective in treating other conditions. For been a prominent etiological theory of major depressive dis example, antidepressants have been demonstrated to be effec order for the past few decades and support for this has been tive in the treatment of hot flashes associated with meno strengthened by the effectiveness of medications that enhance pause, pain and Smoking cessation. monoamine activity, particularly those which are serotoner (0012. Anxiety Disorder gic and/or noradrenergic. However, any given antidepressant 0013 Anxiety disorder is a group of disorders which is only effective in a subset of depressed patients and often affect behaviour, thoughts, emotions and physical health. only partially so. Current treatments administered in con Anxiety disorder is believed to be caused by a combination of trolled trials in academic settings with selected Samples show biological factors and an individual's personal circumstances. efficacy in only about 60% of patients and only about half of People suffering from anxiety disorder are subject to intense, these have full remission of symptoms. This is important prolonged feelings of fright and distress for no obvious rea since the presence of residual symptoms is a strong predictor son. The condition turns their lives into a continuous journey of relapse. There are other physiological changes associated of unease and fear and can interfere with their relationships with major depressive disorder which suggest a more com with family, friends and colleagues. US 2012/O 190743 A1 Jul. 26, 2012

0014 Anxiety disorder is among the most common of all monitored for this on a regular basis and so colorectal cancer mental health problems. It is estimated that it affects approxi is usually detected much earlier than in the general popula mately 1 in 10 people. It is more prevalent among women than tion. among men, and affects children as well as adults. It is com (0023 The treatment of IBD depends on the severity of the mon for people to Suffer from more than one type of anxiety particular condition. IBD may require immunosuppression or within the category of anxiety disorder, and for an anxiety a form of mesalamine. Often, Steroids are used to control disorder to be accompanied by depression, eating disorders disease flare-ups. TNF inhibitors can also be used for both and/or substance abuse. Crohn's disease patients and patients with ulcerative colitis. Severe cases may require Surgery, Such as bowel resection, 0015 Types of anxieties falling within the category of strictureplasty or a temporary or permanent colostomy or anxiety disorder include panic disorder (in which panic ileostomy. attacks occur without warning, accompanied by Sudden feel 0024. The goal of treatment is to achieve remission, after ings of terror and physical symptoms including chest pain, which the patient is usually Switched to a less potent drug with heart palpitations, shortness of breath, dizziness, abdominal fewer potential side effects. Occasionally, an acute resur discomfort, feelings of unreality and fear of dying) and social gence of the original symptoms may appear. Depending on and specific phobias (the former involving a paralysing, irra the circumstances, it may go away on its own or require tional self-consciousness about Social situations and the latter medication. The time between such resurgences may be any involving specific phobias. Such as unreasonable fear of fly where from weeks to years, and varies widely between ing, blood or heights). patients. 0016. Another type of anxiety disorder is post-traumatic (0025 Irritable Bowel Syndrome stress disorder, which may be caused by a terrifying experi 0026 Irritable bowel syndrome (IBS) is a disorder char ence in which serious physical harm occurred or was threat acterized most commonly by cramping, abdominal pain, ened. Survivors of rape, child abuse, war or a natural disaster bloating, constipation and/or diarrhea. IBS causes a great deal may develop post-traumatic stress disorder. Common Symp of discomfort and distress, but it does not permanently harm toms include flashbacks, during which the person re-lives the the intestines and does not lead to a serious disease, such as terrifying experience, nightmares, depression and feelings of cancer. Many people can control their symptoms with diet, anger or irritability. stress management, and prescribed medications. For some 0017 Obsessive compulsive disorder is another type of people, however, IBS can be disabling. They may be unable to anxiety disorder. This is a condition in which people suffer work, attend social events, or even travel short distances. from persistent unwanted thoughts (obsessions) and/or rituals 0027. As many as 20 percent of the adult population have (compulsions) which they find impossible to control. Typi symptoms of IBS, making it one of the most common disor cally, obsessions concern contamination, doubting (Such as ders diagnosed by doctors. It occurs more often in women worrying that a household appliance hasn’t been turned off) than in men, and it begins before the age of 35 in about 50 and disturbing sexual or religious thoughts. Compulsions percent of those affected. Sometimes people find that their include Washing, checking, organizing and counting. symptoms subside for a few months and then return, while 0018 Generalized anxiety disorder is another type of others report a constant worsening of symptoms over time. anxiety disorder, in which a person has repeated, exaggerated 0028. There is no specific diagnostic test for IBS, although worry about routine life events and activities. This disorder diagnostic tests may be performed to rule out other problems. often lasts many months, during which time the person is These tests may include stool sample testing, blood tests, and affected by extreme worry more days than not. The individual X rays. Typically, a doctor will perform a sigmoidoscopy or a anticipates the worst, even if others would say he or she has no colonoscopy. The doctor may diagnose IBS based on the reason to expect it. Physical symptoms can include nausea, patient's symptoms, including frequency of abdominal pain trembling, fatigue, muscle tension and/or headache. or discomfort during the past year, when the pain starts and 0019. There are two main medical approaches to treating stops in relation to bowel function, and how bowel frequency an anxiety disorder: (1) drug therapy and (2) cognitive-be and stool consistency have changed. havioural therapy (CBT). Combining the two types of treat 0029. Unfortunately, many people suffer from IBS for a ment can also be effective. Because most anxiety disorders long time before seeking medical treatment. Up to 70 percent have at least some biological component, anti-depressants of people suffering from IBS are not receiving medical care and anti-anxiety drugs are generally prescribed. for their symptoms. Medications are an important part of 0020 Inflammatory Bowel Disease relieving the symptoms of IBS. Such medications include 0021 Inflammatory bowel disease (IBD) is a group of fiber Supplements or laxatives for constipation, medicines to inflammatory conditions of the colon and Small intestine. The decrease diarrhea and antispasmodics to control colon muscle major types of IBD are Crohn's disease and ulcerative colitis. spasms and reduce abdominal pain. In addition, antidepres IBDS may present with any of the following symptoms: sants may relieve Some symptoms of IBS. abdominal pain, vomiting, diarrhea, hematochezia (bright red 0.030 Inflammatory Airway Disease blood in stools) and weight loss. Diagnosis is generally by 0031. Inflammatory airway disease includes asthma and colonoscopy with biopsy of pathological lesions. chronic obstructive pulmonary disease (COPD). Asthma is a 0022 While IBD can limit quality of life because of pain, chronic inflammation of the lungs in which the airways (bron Vomiting, diarrhea, and other socially unacceptable symp chi) are reversibly narrowed. Asthma affects 7% of the popu toms, it is rarely fatal on its own. Fatalities due to complica lation and 300 million people worldwide. During an asthma tions such as toxic megacolon, bowel perforation and Surgical attack, the Smooth muscle cells in the bronchi constrict, and complications are also rare. IBD patients do have an increased the airways become inflamed and swollen. This results in risk of colorectal cancer, although these patients are generally difficulties in breathing. US 2012/O 190743 A1 Jul. 26, 2012

0032 Asthma causes approximately 4,000 deaths a year in 0046) or (I) X is the U.S. Attacks can be prevented by avoiding triggering factors and by drug treatment. Drugs such as inhaled B2 agonists are often used for acute attacks. In more serious H cases, drugs are used for long-term prevention, starting with Y. B - inhaled corticosteroids, and then long-acting B2-agonists if / necessary. Leukotriene antagonists can also be used in place -(CH2), of corticosteroids. Monoclonal antibodies such as mepoli Zumab and omalizumab are sometimes effective. 0047 (J) Y is absent, and C and C together form a 0033 COPD includes a few lung diseases such as chronic double bond, bronchitis and emphysema. Many people with COPD have 0.048 (K) Z is —(CH), , both of these diseases. Symptoms of COPD include shortness 0049 (L) q and rare integers, of breath, increased mucus in the lungs and coughing. The main treatments for COPD are: quitting Smoking, medica 0050 (M) q=0 to 4, tions, such a bronchodilators and corticosteroids and pulmo 0051 (N) r–1 to 13, nary rehabilitation. 0.052 (O) 5sq+rs 13 for all q and 4, and 0034) Urinary Incontinence 0.053 (P) wherein, optionally, there is a second double 0035 Urinary incontinence is the inability to control the bond formed between adjacent methylene groups of for release of urine from the bladder. Some people experience mula (1) wherein each carbon thereof is bonded to at occasional, minor leaks of urine, while others wet their least one hydrogen; clothes frequently. Types of urinary incontinence include 0054 or (O) X is —(CH) , stress incontinence, urge incontinence and overflow inconti 0.055 (R) Z is nence. Treatment for urinary incontinence depends on the type of incontinence, the severity of the problem and the (CH2)(CH3, underlying cause. Treatment may include, for example, A behavioural techniques, physical therapy and/or medications FCC V Such as anticholinergics, topical estrogens and imipramine. H 0036. The limited efficacy, often unacceptable side effects and physiological factors that may induce or otherwise affect the course of the disorders and diseases discussed above make 0056 (S) Y is absent, and C and C, together form a it necessary to continue to search for new compounds with double bond, novel pharmacological actions to address these disorders and 0057 (T) R is -(CH2)CH or is -H, diseases. 0.058 (U) t and u are integers, 0059 (V) t=1 to 5, SUMMARY OF THE INVENTION 0060 (W) u=0 to 12, 0061 (X) 5st--us 13 for all tandu, and 0037. The present invention features a compound having 0062 (Y) wherein, optionally, there is a second double the following the structure: bond formed between adjacent methylene groups of for mula (1) wherein each carbon thereof is bonded to at (1) least one hydrogen, including a pharmaceutically acceptable salt of the com pound. 0063. In one aspect of the invention, A and B are both OH. 0064 V and W can both be oxygen. (0065 Preferably, R is —(CH.)CHs. The value of p can wherein: be from 0 to 2, more preferably p is 0 or 1, and most preferably (i) A and B are independently —OH or —SH, p is 0. (ii) V and W are independently oxygen or sulfur and at least 0066. The value of n can be from 2 to 12 while 7sm-- one of V and W is oxygen, ns 13, or n can be 3 to 11 and 8sm+ns 12, or n can be from (iii) R is -(CH2)CH or is -H, and 4 to 10 and 9sm+ns 11, more preferably, n is 5 to 9 and (iv) p is an integer from 0 to 3, and: m+n=10. The value of m can be from 2 to 4, but is preferably 0038 (A) X is —(CH) , 3. 0039 (B)Y is H, 0067. The value ofr can be from 2 to 12 while 6sq+rs 12, 0040 (C) Z is —(CH), , more preferably r is from 3 to 11 while 7sq+rs 11, more 0041 (D) m and n are integers, preferably r is from 4 to 10 while 8sq+rs 10, and most 0042 (E) m=1 to 5, preferably, r is from 5 to 9 and q+r is 9. 0043 (F) n=4 to 14, 0068. The value of q can be from 1 to 3 and preferably q is 0044 (G) 6sm+ns 14 for all m and n, and 2. 0045 (H) wherein, optionally, there are up to two car 0069. The value of u can range from 1 to 11 while 6st+ bon-carbon double bonds, each double bond formed us 12, more preferably u is from 2 to 10 and 7st+us 11, between adjacent methylene groups of formula (1) more preferably u is from 3 to 9 while 8st--us 10 and most wherein, if there are two said double bonds each carbon preferably, u is 4 to 8 and t+u is 9. thereof is bonded to at least one hydrogen; (0070. The value oft can be from 2 to 4 and is preferably 3. US 2012/O 190743 A1 Jul. 26, 2012

0071. If one or both of two carbon-carbon double bonds of 0078. Another preferred compound is a substantially ste foregoing paragraph (H) are present in the compound, then reochemically pure compound of Formula (I) of the structure: each of those bonds can beformed between methylene groups of Z. A methylene group is —(CH)—. Preferably, if such a

O bond is present, there is only one of them. H 0072. If the second double bond of paragraph (P) is HO present, then the bond is preferably formed between methyl s enegroups of Z. 0073 Most preferably, none of the double bonds of para HO graphs (H) and (P) are present. 007.9 Throughout this specification Formula (I) is often 0074. A preferred compound has Formula (I), this com referred to as 6-methyl myristic acid monoglyceride, more pound being a mixture of all four stereoisomers. When stere often 6-MMAM. When a compound of the invention is oisomers are referred to herein, we are speaking of those that referred to as having Formula (I) with no other descriptors, result from the presence of two chiral centers such as those this means that the compound is a mixture of the four Stere found in the compound of Formula (I) and discussed further oisomers described above. below. 0080. The invention includes a compound of Formula (I) in which the chiral carbon of the glycerol moiety is a mixture of R and S stereochemical configurations while the C-6 car bon of the myristic acid moiety is R. Also included is a Formula (I) compound of Formula (I) in which the chiral carbon of the O glycerol moiety is a mixture of both R and S stereochemical HO 1 configurations while the C-6 carbon of the myristic acid moi O (CH2)6 ety has the S configuration. Further, the invention includes a compound of Formula (I) in which the chiral carbon of the glycerol moiety has the S configuration while the C-6 carbon HO of the myristic acid moiety is a mixture of R and S. Also included is a compound of Formula (I) in which the chiral 0075. A preferred compound is a substantially stere carbon of the glycerol moiety has the R configuration while the C-6 carbon of the myristic acid moiety is a mixture of R ochemically pure compound of Formula (I) of the structure: and S. I0081. The invention includes a pharmaceutical composi tion containing any of the compounds described above. I0082. The pharmaceutical composition can be adapted for oral delivery, parenteral delivery, topical delivery, rectal delivery, vaginal delivery, administration by oral inhalation or nasal delivery. I0083. The invention includes any of the foregoing com pounds in various forms. Particular dosage forms include a Solution, a suspension, a syrup, a tablet, a capsule, micropar 0076 Another preferred compound is a substantially ste ticles, an ointment, a cream or a lozenge, or a capsule, with a reochemically pure compound of Formula (I) of the structure: preferred form being a tablet. I0084. The invention includes a method for treating a dis order or disease associated with neurokinin 2 (NK) receptor O activity. The method includes the step of administering a H HO 1 therapeutically effective amount of any of the foregoing com , 'O s (CH2)6 pounds. When compounds of the invention are referred to herein, it is to be understood that this includes pharmaceuti Hd I cally acceptable salts, whether explicitly stated or not. HO I0085 Disorders or diseases associated with said NK receptor activity treated according to methods of the inven 0077. Another preferred compound is a substantially ste tion can be a depressive mood disorder, anxiety disorder, reochemically pure compound of Formula (I) of the structure: irritable bowel syndrome, inflammatory bowel disease, inflammatory airway disease or urinary incontinence. The disorder or disease associated with said NK receptor activity

can specifically be depressive mood disorder, or it can be major depressive disorder. I0086. The subjector patient may or may not also be treated by psychotherapy concurrently with a method of the inven tion. I0087. Of course a compound of the invention can be con tained in a pharmaceutical formulation that also includes a pharmaceutically acceptable carrier. US 2012/O 190743 A1 Jul. 26, 2012

0088 Administration of a compound described herein can (0103 FIG. 8 shows a chromatogram from an HPLC-UV be accompanied by a therapeutically effective amount of of Fraction 185 of Formulation A. The UV detector was set at another therapeutic agent. 190 nm. The units along the x-axis are time (minutes) and the 0089. Typically, subjects treated using the invention are units along the y-axis are absorbance units (AU). human patients. 0104 FIG. 9 shows a graph of the effect of various con 0090 Another method of the invention is for treating a centrations of 6-methyl-myristic acid 2,3-dihydroxypropyl disorder or syndrome associated with a depressive mood dis ester on binding of neurokinin A (NKA) to the human NK order. The method includes the step of administering a thera receptor (measured as percent of specific binding) as well as peutically effective amount of a compound of the invention to a subject in need thereof. The disorder or syndrome can be a the ICs and K, for NKA and 6-methyl-myristic acid 2,3- disorder of the brain or nervous system, anxiety disorder, dihydroxypropyl ester. sexual dysfunction, Substance abuse, eating disorder or hor 0105 FIG. 10 shows a graph of the effect of various con mone disorder. centrations of myristic acid 2,3-dihydroxypropyl ester on 0091. In another aspect, the invention is a method of treat binding of neurokinin A (NKA) to the human NK receptor ing a disorder or condition treatable by an antidepressant. The (measured as percent of specific binding) as well as the ICso method includes administering a therapeutically effective and K, for NKA and myristic acid 2,3-dihydroxypropyl ester. amount of a compound of the invention a Subject in need 0106 FIG. 11 shows a graph of the effects ofb Ala-NKA thereof. The disorder or condition treatable by an antidepres (4-10) (control), compound #2 (myristic acid 2,3-dihydrox sant can be hot flashes associated with menopause, pain or ypropyl ester) and compound #3 (6-methyl-myristic acid 2.3- Smoking cessation. dihydroxypropyl ester) in a cellular/functional Ca" agonist 0092 Another method of the invention is for modulating assay for the human NK receptor. The X-axis indicates the an activity of an NK receptor comprising contacting the NK log of the compound (M) and the y-axis indicates the % receptor with an effective amount of a compound of the maximal response (RFU). Error bars are ranges for duplicate invention. The method can be an in vivo oran invitro method. data. 0093. The invention includes use of a compound, or a 0107 FIG. 12 shows a graph of the effects of bAla-NKA pharmaceutically acceptable salt thereof, described above for (4-10) (control), GR159897 (control), compound #2 (myris treatment of a disorder or disease, etc. as described above in tic acid 2,3-dihydroxypropyl ester) and compound #3 (6-me connection with various methods of the invention. thyl-myristic acid 2,3-dihydroxypropyl ester) in a cellular/ 0094. An inventive use of a compound of the invention is functional Ca" antagonist assay for the human NK2 receptor. thus also in the manufacture of a medicament for treatment of The x-axis indicates the log of the compound (M) and the such a disorder or disease, etc. y-axis indicates the '% maximal response (RFU). Error bars are ranges for duplicate data. BRIEF DESCRIPTION OF THE FIGURES 0095. The person skilled in the relevant art(s) will under DETAILED DESCRIPTION OF THE INVENTION stand that the figures, described below, are for illustration 0108. In accordance with the present invention, the com purposes only. The figures are not intended to limit the scope pounds of the invention and uses to treat disorders or diseases of the invention in any way. associated with neurokinin (NK) receptor activity are 0096 FIG. 1 shows an HPLC chromatogram of a fertilized described. egg isolate according to embodiments of the present inven 0109 As used herein, the term “pharmaceutically accept tion. able salt' is a salt formed from an acid and a basic group of a 0097 FIG. 2 shows the results of analyses of a fertilized compound having a structural formula of the invention. Illus egg isolate according to embodiments of the present inven trative salts are knownto one skilled in the art and include, but tion. are not limited, to hydrochloride, Sulfate, citrate, acetate, 0098 FIG. 3 shows a graph of the effect of various con oxalate, chloride, bromide, iodide, nitrate, bisulfate, phos centrations of a fertilized egg isolate Sample #20 Top Isolate phate, acid phosphate, isonicotinate, lactate, salicylate, acid (ug/mL) on binding of neurokinin A (NKA) to the human citrate, tartrate, oleate, tannate, pantothenate, bitartrate, NK receptor (measured as percent of specific binding) as ascorbate. Succinate, maleate, gentisinate, fumarate, glucon well as the ICs and K, for NKA and Sample #20 Top Isolate. ate, glucaronate, saccharate, formate, benzoate, glutamate, 0099 FIG. 4 shows a bar graph of the binding activity of methanesulfonate, ethanesulfonate, benzenesulfonate, various fractions and a control sample of Formulation A p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2- (eluted from an HPLC) to the human NK receptor. Binding hydroxy-3-naphthoate)) salts. activity was measured as the percent inhibition of binding by 0110. According to this invention, the chemical structures the ligand NKA. depicted herein, including the compounds of this invention, 0100 FIG. 5 shows a chromatogram from an HPLC-UV encompass all of the corresponding compounds enantiomers of Fraction 171 of Formulation A. The UV detector was set at and Stereoisomers, that is, both the stereomerically pure form 210 nm. The units along the X-axis are time (minutes) and the (e.g., geometrically pure, enantiomerically pure, or diastereo units along the y-axis are absorbance units (AU). merically pure) and enantiomeric, diastereomeric, and geo 0101 FIG. 6 shows a chromatogram from an HPLC-UV metric isomeric mixtures and as such, are also compounds of of Fraction 185 of Formulation A. The UV detector was set at the invention. Methods for separating one enantiomer from 210 nm. The units along the X-axis are time (minutes) and the another are known to those skilled in the art. In some cases, units along the y-axis are absorbance units (AU). one enantiomer, diastereomer, or geometric isomer will pos 0102 FIG. 7 shows a chromatogram from an HPLC-UV sess Superior activity or an improved toxicity or kinetic pro of Fraction 171 of Formulation A. The UV detector was set at file compared to others. In those cases, such enantiomers, 190 nm. The units along the x-axis are time (minutes) and the diastereomers, and geometric isomers of a compound of this units along the y-axis are absorbance units (AU). invention are preferred. US 2012/O 190743 A1 Jul. 26, 2012

0111. The compounds of the invention, including any Rating Scale, the Beck Depression Inventory, the Arizona enantiomers of Such compounds, may be substantially pure. Sexual Experience Scale, or the General Health Question A compound is “substantially pure' when it is separated from naire Scoring (Short-Form 36), each of which is known to one the components that naturally accompany it. Thus, for skilled in the art and is described in further detail herein as example, a compound of Formula (I) that is isolated from compared to the rating in the Subject who has not been treated fertilized egg isolate will generally be substantially pure with a compound of the invention. when it is separated from other components of the fertilized 0116 For a subject with anxiety disorder, a “beneficial egg isolate. Typically, a compound is Substantially pure when outcome includes a decrease in the rating of a Subject on the it is present in at least 60%, 70%, 75%, 80%, 85%, 90%. 95% Hamilton Anxiety Rating Scale, decreased feelings or or 99%, by weight, of the total material in a sample. A sub decreased frequency of feelings of distress and fright, stantially pure compound can be obtained, for example, by decreased number and/or duration of panic attacks, decreased extraction from a natural source, such as a fertilized egg avoidance of Social situations, decreased fears associated isolate or by chemical synthesis. Purity can be measured with specific phobias, decreased occurrence and duration of using any appropriate method Such as column chromatogra flashbacks, nightmares, depression and feelings of anger or phy, gel electrophoresis, high pressure liquid chromatogra irritability associated with post-traumatic stress disorder and phy (HPLC), etc. decreased occurrence of obsessions and/or compulsions as 0112 The compounds of the invention can be used to treat compared to the subject who has not been treated with a a disorder or disease associated with NK receptor activity. A compound of the invention. compound of the invention is administered in a therapeuti 0117 For a subject with inflammatory bowel disease, a cally effective amount to a subject in need thereof. “beneficial outcome includes decreased abdominal pain, 0113. The term “treat” means improving the disorder or Vomiting, diarrhea, hematochezia and/or weight loss as com disease of a patient to whom a compound of the present pared to a Subject who has not been treated with a compound invention is being administered. The term “treatable” means of the invention. capable of improving the disorder, disease or condition of a 0118 For a subject with irritable bowel syndrome, a “ben patient to whom a compound of the present invention is being eficial outcome includes a decrease in cramping, abdominal administered. These term include ameliorating the disorder, pain, bloating, constipation, and/or diarrhea as compared the disease or condition, for example, by obtaining a beneficial subject who has not been treated with a compound of the outcome, and Such amelioration can be determined using invention. standard tests known in the art. The terms also include pre 0119 For a subject with inflammatory airway disease, a venting the disorder or disease from occurring or re-occur “beneficial outcome' includes decreased shortness of breath, ring, such as in prophylactic or maintenance therapy. decreased mucus in the lungs and/or decreased frequency 0114. As used herein, the term “NK receptor-associated and/or duration of coughing spells as compared to the Subject disorder or disease' refers to a disorder or disease associated who has not been treated with a compound of the invention. with inappropriate, e.g., greater or less than normal, NK I0120 For a subject with urinary incontinence, a “benefi receptor activity. The greater than normal NK receptor activ cial outcome includes decreased leaking or urine and/or ity may result from increased activity of a normal number of wetting of clothes as compared to the Subject who has not NK receptors in the Subject, or could result from a greater been treated with a compound of the invention. than normal number of NK receptors in the subject with the I0121 The precise amount of compound administered to a NK receptor-associated disorder or disease. The less than subject will depend on the type and severity of the disorder or normal NK receptor activity may result from decreased disease and on the characteristics of the Subject, such as activity of a normal number of NK receptors in the subject, or general health, age, sex, body weight and tolerance to drugs. could result from a less than normal number of NK receptors The skilled artisan will be able to determine appropriate dos in the subject with the NK receptor-associated disorder or ages depending on these and other factors. disease. NK receptor-associated disorders or diseases I0122. As used herein, the terms “subject”, “patient' and include, for example, major depressive disorder, anxiety dis "animal’ are used interchangeably and include, but are not order, irritable bowel syndrome, inflammatory bowel disease, limited to, a cow, monkey, horse, sheep, pig, chicken, turkey, inflammatory airway disease and urinary incontinence. An quail, cat, dog, mouse, rat, rabbit, guinea pig and human. In NK receptor-associated disorder or disease may include a one embodiment, the Subject, patient or animal is a mammal. disorder or disease that is mediated, at least in part, by an NK In another embodiment, the preferred Subject, patient orani receptor. mal is a human. 0115. An “effective amount' is the quantity of compound Methods for Isolating a Compound of the Invention: in which a beneficial outcome is achieved when the com pound is administered to a subject with a disorder or disease I0123. A compound having the structure depicted by For associated with NK receptor activity or alternatively, the mula (I) can be isolated from fertilized egg isolates as quantity of compound that possesses a desired activity in vivo described below. or in vitro. In the case of a disorder or disease associated with 0.124 Fertilized Egg Isolates—Preparation NK receptor activity, a beneficial outcome includes reduc 0.125. In the preparation of a fertilized egg isolate from tion in the extent or severity of the symptoms associated with which the compound of Formula (I) can be isolated, at least the disease or disorder and/oran increase in the quality of life one fertilized egg is incubated for anywhere from about 3 to of the subject compared with the absence of the treatment. For about 15 days, more preferably about 3 to about 5 days, or example, for a Subject with major depressive disorder, a “ben more preferably about 6 to about 12 days, and even more eficial outcome includes a decrease in the rating of a subject preferably about 7 to about 9 days, from the day the egg is on the Hamilton Depression Rating Scale, the Hamilton fertilized. Generally speaking, the fertilized egg is incubated Anxiety Rating Scale, the Montgomery-Asberg Depression for a period of time that allows angiogenesis to initiate and/or US 2012/O 190743 A1 Jul. 26, 2012 the embryo to mature to the point that embryos are visible to The embryo can be substantially separated from the white the naked eye. The eggs can be from a variety of origins, for albumen portion manually or other Suitable means as deter example, avian, reptilian, or from egg-laying mammals. Gen mined by the skilled person. It will be recognized by those erally speaking, any egg from which an embryo or blood skilled in the art that the embryo can be substantially sepa vessels associated with an embryo can be removed can be rated from the white albumen portion and the rest of the inner Suitable. The eggs are preferably avian eggs, and can be contents at the same time. For example, the embryo can be obtained from any bird that has been bred for egg production, manually removed from the white albumen portion and rest of Such as chicken, geese, ducks, and the like. Chicken eggs are the inner contents using tweezers or other Suitable instrument. preferred for reasons including their availability and ability to In some cases, the embryo can be manually peeled off the be mass produced. Incubation can occur in any environment, yolk sac, which forms part of the rest of the inner contents. So long as the eggs are kept at a temperature for extended 0.130. Once the embryo is substantially separated from the periods of time that allows maturation of the embryo. Suitable white albumen portion and the rest of the inner contents of the temperatures for incubation are in the range of about 20°C. to egg, the embryo is optionally washed at least once with a about 60°C., more preferably in the range of about 25°C. to suitable solvent, such as a buffer solution, sterile deionized about 55°C., and more preferably in the range of about 35°C. water, or any Suitable saline solution. For example, sterile to about 45° C. Once the eggs are incubated for a period of phosphate buffer saline (PBS) can be used. time, they are optionally treated to reduce external microflora I0131. It will be understood for the following methods that or otherwise Sterilized by any suitable means, such as wash reference to contents of the egg may actually be a reference to ing the egg shells with a solvent Such as ethanol, for example, the retentate if the contents have been subjected to a filtration an about 50% to about 95% solution of ethanol, with subse process. It will also be understood that a whole fertilized egg quent time allowed to permit evaporation or drying of the can be cracked, the shell removed, and the whole of the Solvent, or by rotating the eggs under an ultraviolet (UV) light shelled egg frozen and freeze-dried according to any of the source for a suitable period of time. Any solvent is preferably procedures described above and below, to produce a fertilized evaporated before further manipulation of the egg. The eggs egg isolate. Also, more than one whole fertilized egg can be are then cracked to access the inner contents. The eggs can be cracked, shells removed, the whole of the shelled fertilized cracked under aseptic conditions either manually or using a eggs combined and blended into a slurry, and frozen and suitable mechanical device. This procedure and/or all or most freeze-dried according to any of the procedures described of the procedures described above and below can be con above and below. ducted in a cooled atmosphere, Such as an atmosphere of 0.132. The contents of the eggs or the embryos are placed about 5° C. in at least one freezable container. The container can be, for 0126 The contents of the egg are collected in a container, example, a test tube, Petri dish, beaker, stainless steel tray, or Such as a stainless steel container, which is preferably steril plastic container. It is preferred that the contents or embryos ized and/or chilled. The contents from the container or from are frozen very soon after being removed from the shell, such the egg can optionally be subjected to a filtration process, for as within about 2 hours, more preferably within about 1 hour, example, by being placed on a mesh. The mesh openings can and even more preferably within about 0.5 hours, or as soon be about 0.5 to about 4 millimeters, more preferably about 1 as possible. Depending on how long the contents or embryos millimeter. The mesh is preferably sterile. are to be frozen, the freezing temperature should be in the 0127 Optionally, the contents of the egg and/or some or range of about -50° C. to about 10°C., more preferably in the all of the broken shell can be placed directly on the mesh. The range of about -40°C. to about 5°C., and even more prefer contents of the egg and/or some or all of the broken shell are ably in the range of about -35° C. to about -25°C. It is allowed to filter on the mesh for a period of time such that preferred that the contents or embryos are frozen for at least there is substantially no further dripping of fluid through the about 6 hours, more preferably at least about 12 hours, even mesh. The broken shell can be removed from the contents of more preferably at least about 24 hours. The frozen contents the egg before, during, or after the filtration process. After the or embryos may be freeze-dried or lyophilized after a period filtration, the Solid or Solid and semi-solid retentate can com of time. The contents or embryos can be completely frozen prise the embryo, vascular connective tissue, a Substantial before the freeze-drying/lyophilizing step. portion or all of the albumen, a substantial portion or all of the I0133) Optionally, frozen or unfrozen contents or embryos chalaza, and the clear sac. Semi-solid retentate can comprise can be pooled in a suitable container, such as a beaker, or a Solid material as well as a viscous material. Such as a gelati plastic container, and mixed or blended with a suitable sol nous material, for example, albumen. The retentate or semi vent, if necessary, to form a slurry. The solvent can be suitably Solid retentate can be optionally washed at least once with a aqueous to wet the mixed contents or embryos and be able to suitable solvent, such as a buffer solution, sterile deionized be frozen in a standard laboratory freezer. Suitable solvents water, or any Suitable saline solution. For example, sterile include water, aqueous buffer, and the like. To form the slurry, phosphate buffer saline (PBS) can be used. it is preferred that the contents and/or embryos are blended. 0128. The retentate can be collected from one egg and then The contents or embryos can be blended or homogenized freeze-dried according to the processes described herein, or with, for example, a hand-held blender or other suitable the retentate can be collected from one or more eggs together, means. The slurry can then be frozen as described above and and then freeze-dried according to the processes described freeze-dried. Freeze-drying is preferably performed at an herein. ultimate temperature in the range of about -80° C. to about 0129. The white albumen portion and/or embryo can be -10° C., more preferably in the range of about -65° C. to substantially separated from the rest of the contents of the about -15°C., and even more preferably in the range of about egg. The white albumen portion may be substantially sepa -40°C. to about -20°C. and a pressure of about 500 millitorr, rated from the rest of the contents by any Suitable means, such or other suitable pressure as can be determined by the skilled as decantation of the white albumen portion, or by Suction. person. The freeze-drying process is preferably maintained at US 2012/O 190743 A1 Jul. 26, 2012

the ultimate temperature for a period of in the range of about hydrophilic molecules in the solution are dissolved in the 1 to about 6 hours, more preferably in the range of about 2 to aqueous solution. The aqueous solution can be of a Substan about 5 hours, and even more preferably in the range of about tially equal volume to the slurry, but volumes of 1.5 times, 2 3 to about 4 hours. The whole freeze-drying process is typi times, or even 3 times the volume of the slurry can be used. cally conducted for a period in the range of about 15 to about Optionally, the mixture can be warmed slightly during the 45 hours, more typically in the range of about 25 to about 35 mixing step. After the mixing, the aqueous solution can be hours, and even more typically in the range of about 28 to Substantially clarified by Substantially removing any solid about 32 hours. portions in the mixture by Suitable means such as centrifuga 0134. The freeze-dried contents, freeze-dried embryo, or tion or filtration. The clarified aqueous portion can then be freeze-dried slurry is then dispersed and/or pulverized if nec frozen and freeze dried to produce a powder that is optionally essary to form a Substantially homogeneous powder. The sterilized according to methods described herein. contents that were freeze-dried individually or in smaller 0.139. The slurry produced by any of the methods groups can be combined together before or after the pulveri described above can be mixed with a substantially hydropho Zation step to form a Substantially homogeneous powder. The bic solvent. The substantially hydrophobic solvent is prefer pulverization can be done, for example, mechanically using a ably chilled. Suitable hydrophobic solvents include, for Suitable machine, such as a coffee bean grinder or a hammer example, ether, chloroform, hexane, petroleum ether or mill, or manually using a suitable tool. Such as a glass rod. A acetonitrile. For example, ether, especially diethyl ether, can suitable sterilization should be one that does not adversely be used. The slurry is mixed with the hydrophobic solvent for affect certain freeze-dried components. a period of time as described above. As will be recognized by 0135) In association with any process described herein, a person skilled in the relevant arts, any steps of a process preservatives to control microbial growth can be blended into using a substantially hydrophobic solvent should be con the powder or concentrate before it is stored. Preservatives ducted in a fume hood or similar device, and the solvents can also be added at another stage of the manufacture, includ should be kept away from open flames or heat sources. After ing before the freeze-drying or concentration step instead of the mixing period, the solid portions of the mixture can be or in addition to, being added to the powder or concentrate. substantially removed from the solvent portion by suitable Suitable preservatives include common food preservatives means such as centrifugation or filtration. The solvent portion such as 0.5% w/w sodium benzoate and 0.2% w/w potassium will comprise substantially a hydrophobic solvent portion sorbate. Other suitable preservatives could be selected by the and may also comprise an aqueous portion. The solvent por skilled person. tion can be transferred to a separating funnel or essentially 0136. The powders produced by the processes disclosed equivalent device to separate the aqueous portion from the herein can be stored in Suitable, Substantially air-tight con hydrophobic solvent portion. If the top layer is the hydropho tainers. Suitable containers include plastic bags, barrels, plas bic solvent portion, it can be siphoned off the top or removed tic containers, bottles, combinations thereof, and the like. For from the separating funnel after the bottom aqueous layer is example, the powder can be packaged under controlled, asep removed. Alternatively, the bottom aqueous portion can be tic conditions into sterile polyethylene/polypropylene bottles frozen, thereby allowing the top ether-based layer to be with tamper-proof security seals. The powder can be stored decanted. The aqueous portion can be extracted a number of under a substantially dry, inert gas, such as nitrogen. It is times, for example, about 3 times, with the hydrophobic sol preferred that the powder be stored at room temperature or vent. The hydrophobic solvent can be of substantially equal cooler, for example, at a temperature in the range of about 10 Volume to the aqueous portion, or can be 1.5 times, 2 times or C. to about 25°C., more preferably in the range of about 15° even 3 times the volume of the aqueous solvent. Other ratios C. to about -20°C. For long term storage, it is preferred that may also be suitable. the powder is stored at a temperature of about -10° C. or 0140. After the extraction process, all of the hydrophobic below, or, more preferably, -20°C. or below. The powder can isolates can be pooled and concentrated by a Suitable method. be stored for a period of time in a substantially desiccated The concentrated isolates can be stored at a temperature atmosphere. The powder can also be vacuum-packed. below room temperature, such as about 5° C. in a suitable 0.137 A slurry can also be prepared by separating the container that is Substantially sealed from the atmosphere, contents or embryos of at least one fertilized egg from the egg Such as a sealed vial. shell, and pooling the separated contents or embryos in a 0.141. The slurry produced by any of the methods Suitable container. The separated contents or embryos can be described above can be clarified before an extraction proce cooled during this step. For example, the container can be dure. Preferred clarification steps include methods of filtra placed on ice to facilitate cooling. The contents or embryos tion, using Such filters as sieves or filter papers or pads. Other can be blended by methods described above to produce a clarification steps can include methods of centrifugation. A slurry. The slurry can be freeze-dried as described above, or filter aid, such as Superflow DETM can be added to the filtrate partially or wholly used for extraction procedures as follows. produced by the filtering step before further clarification. 0.138. The slurry may also be mixed with an aqueous solu Some of the resultant filtrate can be frozen in suitable con tion for a period of time. The aqueous solution may comprise tainers for freeze-drying. Also, some of the resultant filtrate water, an aqueous buffer, or any other aqueous solvent. If the can be mixed with a hydrophobic solvent as described above aqueous Solution comprises water, it is preferred that the so that an aqueous layer and a hydrophobic layer are formed. water is distilled and, more preferably, also deionized before The layers can be separated, concentrated, and stored as use. For example, the water can be treated using reverse described herein. osmosis (R.O.). The slurry and the aqueous solution can be 0142. The fertilized egg isolate prepared by various pro mixed, for example, by stirring for a period of time, the period cesses described herein can be concentrated by repeated of time being in the range of about 5 to about 60 minutes, aqueous and/or hydrophobic solvent extraction. more preferably in the range of about 10 to about 45 minutes, 0143. The compound having the structure depicted by For and even more preferably in the range of about 15 to about 40 mula (I) can be isolated from the fertilized egg isolate using, minutes. It is desired that the aqueous solution has sufficient for example, standard column chromatography techniques. exposure to the contents of the slurry So that any Substantially For example, a slurry of the fertilized egg isolate can be US 2012/O 190743 A1 Jul. 26, 2012

prepared as described above and freeze-dried. The freeze dried product can then be pulverized in a grinder and, if -continued desired, mixed with one or more preservatives such as sodium O benzoate (e.g., 0.5% w/w) and/or potassium Sorbate (e.g., 0.2% w/w). The finished powder can then be loaded onto a s: O 21 N. (CH2)61. high pressure liquid chromatograph (HPLC) column and O eluted with a suitable solvent, for example, various concen trations of methanol or acetonitrile or a mixture of solvents. The compound fraction of the eluate is collected and dehy -- drated, if desired, or subjected to additional rounds of column chromatography, using, for example, a different column, a rt genation different solvent or a different concentration of solvent. 0144. The purity of the desired fractions can be monitored 'pte lysis using, for example, HPLC, or other methods known to those O skilled in the art and the fraction can be further purified, if desired, using techniques known to those skilled in the art. HO. -- 1. 0145 Once a fraction or a combination of fractions is O (CH2)6 Sufficiently pure, the structure of the active compound and its biological activity can be confirmed using methods known to HO those skilled in the art. For example, the biological activity of 6-MMAM2 the active compound can be evaluated using NK receptor binding assays and/or receptor activity assays known to those skilled in the art. 0148 1. The dioxolane of Step III is available from Sigma Aldrich, St. Louis, Mo., U.S.A., or can be prepared accord Synthesis of Compounds of the Invention ing to the route shown in Scheme B. 0149 2. For brevity, 6-methyl myristic acid monoglycer 0146 A stereoisomeric mixture of the preferred com ide is referred to herein as 6-MMAM. 6-MMAM is also pound of the invention, 6-methyl myristic acid monoglycer known as 6-methyl myristate 1-glyceride and 6-methyl ide, was synthesized according to Scheme A. glycidyl myristate. 0147 Racemic 2-methyldecanal 19009-56-4 was thus allowed to react with triphenylposphonium butanoic acid bro mide 17857-14-6 to afford after purification 6-methyl-4- Scheme B ene-tetradecanoic acid. The analogous acid chloride was pre HO pared with thionyl chloride and treated directly with racemic HO ) isopropylidene glycerol then subjected to hydrogenation. The O s: isopropylidene was removed with HCl to obtain 6-methyl H/H2O myristate 1-glyceride as a mixture of Stereoisomers. HO OH -- X

Scheme A O O 0150. 6-MMAM has two chiral centers and therefore exists as four stereoisomers: H -- " Phs-P'-CH3Br a OH

will O

HO 21 N. rock US 2012/O 190743 A1 Jul. 26, 2012 10

could be introduced in Step B of Scheme C, the Hinoue et al. process, for R'-R-methyl rendering unnecessary Step A of -continued Scheme C. 0156 Examples of hydrolysis of 1,3-dioxolanes under mild conditions, Step III of Scheme A, are described, for example, by J. Sun, Y. Dong, L. Cao, X. Wang, S. Wang, Y. Hu, J. Org. Chem., 2004, 69:8932-8934 and R. Dalpozzo, A. De Nino, L. Maiuolo, A. Procopio, A. Tagarelli, G. Sindona, G. Baroli, J. Org. Chem., 2002, 67:9093-9095. 0151. The synthetic route shown in Scheme A produces a (O157. The second chiral center (C") in 6-MMAM is intro mixture of all four stereoisomers, but can be modified to duced in the first step of Scheme A, 2-methyldecanal. obtain stereoisomers of 6-MMAM. 0158. The synthesis of Scheme A can be varied to obtain 0152 Step III of Scheme Acanthus be modified by use of other compounds of Formula (1), as shown in Scheme D. either of the stereoisomers (R- or S-isomer at C*) of the 2,2-dimethyl-1,3-dioxolane shown, or other suitable 1,3-di Scheme D oxolane. U.S. Pat. No. 6,143,908, Hinoue et al., describes a process for preparation of 1,3-dioxolane-4-methanol com O O pounds according to Scheme C. H1NC1\1\1\1\ls. p-p-chi:Br ~us OH R Scheme C

X ~~ O rol - - O O OH HO 21 N. R1 R2 ---> (1) (2) spot

RO s: O

SXR1 R2 (3)

(4)

0153. Hinoue et al. state that preferred examples of com pound (I) of Scheme C are 3-chloro-1,2-propanediol and 3-bromo-1,2-propanediol, and that R' and R of the com rtenin pound can be the same or different and be hydrogen, C-C, alkyl, or phenyl. The dioxolane introduced in Step III of Scheme A corresponds to that in which R' and R are both 'ption methyl groups in Scheme C. In other words, the use of O acetone in Step A of Scheme C will result in the formation of the dioxolane shown in Scheme A. Hinoue et al. demonstrate HO s: --~~ -- Y the preparation of (S)-2,2-dimethyl-1,3-dioxolane-4-metha O iri? nol using (R)-3-chloro-1,2-propanediol as the starting com R pound in Scheme C. HO 0154 (R)-3-chloro-1,2-propanediol (CAS No. 57090-45 6) and (S)-3-chloro-1,2-propanediol (CAS No. 60827-45-4) 0159. Materials can be selected according to the general are available from TCI America, 921 1 N. Harborgate Street, ized formulae shown in Scheme D to obtain a compound of Portland, Oreg. 97203, U.S.A, so these could be used to the invention having Formula (1) in which A and B are each produce (S)-2,2-dimethyl-1,3-dioxolane-4-methanol and —OH, V and Ware each oxygen, X is —(CH) - (m=3).Y (R)-2,2-dimethyl-1,3-dioxolane-4-methanol. is —H, and Z is —(CH) (n=7). The skilled person would 0155 (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane vary reaction conditions for each step to Suit the particular (CAS No. 57044-27-3) and (S)-4-chloromethyl-2,2-dim materials selected. ethyl-1,3-dioxolane (CAS No. 60456-22-6) are available 0160 The preferred compound of the invention, 6-methyl from Ivy Fine Chemicals Corporation of 1879 Old Cuthbert myristic acid monoglyceride, can also be synthesized accord Road, Suite 23, Cherry Hill, N.J. 08034, USA. Either of these ing to, for example, Scheme E. US 2012/O 190743 A1 Jul. 26, 2012

Scheme E

OH O O COCl. I TEA HO C C C II (1) (2) O O

BO --~~ PPh3CI - PhiIII BnO --~~ C (4) (3) rook O 1 O ra. O --~~. V BO N (CH2)61.

viso it O O

- --- - 1 C N (CH2)6 VII HO N (CH2)6

(8) (7) al-O VIIIHO TEA O

O

s: O N (CH2)61 O)- Ph (9) H2O/HC1/CH3CN IX

O

HO 1. r N (CH2)6 HO (10) US 2012/O 190743 A1 Jul. 26, 2012 12

-continued O HON. 1 O (CH2)6

HO 6-MMAM

0161 1. The dioxolane of Step VIII can be prepared (0165. The second chiral center (C") in 6-MMAM is intro according to the route shown in Scheme B. duced by reduction of the double bond in StepX in Scheme E. (0162. 2. R. O. Adlof, W. E. Neff, E. A. Emken, and E. H. Compound (6), the product of Step V of Scheme E, would be Pryde, Journal of the American Oil Chemists' Society, 1977, 54(10):414-416. prepared under conditions in which the longer alkyl chains 0163 The synthetic route shown in Scheme E would pro are formed trans to each other as exemplified in the illustrated duce a mixture of all four stereoisomers, but can be modified Wittig reaction. Asymmetric hydrogenation of the C=C to obtain each of the four stereoisomers. bond will result in formation of either the R— or S- con 0164. Step VIII of Scheme E can thus be modified as figuration at C-6 of the 6-MMAM. Asymmetric hydrogena described in connection with Step III of Scheme A, and tion across C=C bonds is well known. See, for example, U.S. Scheme C. Pat. No. 6,878,665 of de Paule et al.

Scheme F

OH O O

CH COC 2 --- C --- C --it'sn TEA II C O O

BO --- (CH2)YPPh;C - PPhI - BO -- (CH2)No rtuos O O O (C2)n-I - PPh3C S CA (CH2)- BO-- Sa''" R VZ CH Bo1'n 1 4,R. Z-CH voir O O R R COC C (CH-- 4 - VII 2. HO (CHyle?, 1. Z-CH Z-CH

VIIIHO TEA O-K) US 2012/O 190743 A1 Jul. 26, 2012 13

-continued

IX

HO Z-CH,

HO

HO

HO R

0166 Materials can be selected according to the general ized formulae shown in Scheme F to obtain a compound of -continued the invention having Formula (1) in which A and B are each O —OH, V and W are each oxygen, R is (CH2)CH, or is —H. p is an integer from 0 to 3, X is —(CH2). , Y is —H. --- (CH2) (CH2), Z is —(CH), , and mand n are integers in which m=1 to 5 HO Syen-i Q. and n=4 to 14. The skilled person would vary reaction con ditions for each step to Suit the particular materials selected. R 0167 Astereochemically pure compound of the invention A3 is one in which at least 90% of the compound has the desired stereochemistry e.g., Rat C" and Sat C*, or R.S. at C" and R at C, etc. More preferably, the compound is at 92% stere ochemically pure, more preferably still, 94% stereochemi acid halide of A3 cally pure, more preferably still, 96% stereochemically pure, more preferably still, 98% stereochemically pure, and most preferably greater than 99% stereochemically pure. A sub stantially stereochemically pure compound is one that is at least 96% of the desired optically active stereoisomer(s). 0168 A process for preparing a compound of Formula A6 O A4 or A7 is illustrated in Scheme G. The process includes react ing compound A1 and A2 to form alkenyl compound A3. The lucts (CH2). acid halide of A3 is then formed, and reacted with dioxolane O Š4\c1 A4 to form A5, which can then be hydrolyzed to form A6, or O the C=C double bond of A5 reduced, with subsequent O R hydrolysis of the dioxolane, to form the compound A7 R2 R3 Scheme G A5 O hydrolysis O reduction Brr ls - (C2)b (CR2)a H C1 N. HO N-P-Phs O R hydrolysis A1 HO --it's -(CR2)b ydroly A2 O C1 N. R HO US 2012/O 190743 A1 Jul. 26, 2012 14

mic disorder, depressive phase of bipolar disorder, depression due to a general medical condition Such as depression asso -continued ciated with dementia or schizoaffective disorder, substance induced depression and seasonal affective disorder, anxiety HO --- “Syl-n- (Cy disorders, such as generalized anxiety disorder, Social phobia and panic disorder, and sexual dysfunction. k (0173 As also described in PCT publication number WO HO 2009/086634, it has been determined that the fertilized egg isolate as described herein antagonizes the binding interac tions of certain ligands with their receptors. In particular, it in which: a is an integer from 1 to 3: b is an integer from 1 to has been found that the fertilized egg isolate has the capacity 11:4sa+bs 12, and R is -(CH2)CH; and p is an integer to displace the neurotransmitter neurokinin A (NKA) from its from 0 to 3. Preferably, p is 0. R and R can be the same or receptor, the neurokinin 2 (NK) receptor. different, and can be any convenient group Suitable for the 0.174. A number of diseases and conditions are known to reaction. Specific groups include those disclosed by Hinoue: be associated with modulation of the NK receptor. Such hydrogen, C-C alkyl, or phenyl. diseases or conditions include depressive mood disorders, 0169. The R or Sistereoisomer of dioxolane A4 can be used Such as major depressive disorder (see, for example, Dableh, to obtain A6 or A7, as desired, that is stereochemically pure at Ahlstedt, Michale, Louis, Steinberg, Salomé, Holmes, Stein C-2 of the glycerol moiety of A6 or A7. berg, Husum), anxiety (see, for example, Ahlstedt, Michale, Louis, Greibel, Steinberg, Stratton, Teixeira, Walsh, Salomé, Functional Analogs of the Compound of Formula (I): Holmes), irritable bowel syndrome and inflammatory bowel disease (see, for example, Ahlstedt, Lecci, Evangelista, Tou 0170 Functional analogs of the compound of Formula (I) louse), inflammatory airway disease, such as asthma or can be made using methods known to those skilled in the art. chronic pulmonary obstructive disorder (COPD) (see, for For example, the compound of Formula (I) isolated and iden example, Bai, Pinto, Khawaja) and urinary incontinence (see, tified or synthesized according to the methods described for example, Ahlstedt, Rizzo). Furthermore, it has been above may be subjected to directed or random chemical shown that antagonists of the NK receptor, such as saredu modifications, such as replacement of hydrogen by halogen, tant (SR 48964) can be used to promote antidepressant-like replacement of an alkyl by a different alkyl, replacement of effects (Salomé, Dableh, Steinberg, Michale, Louis) and alkoxy by alkyl, replacement of alkyl by alkoxy, acylation, anxiolytic effects (Teixeira, Salomé, Griebel, Michale, alkylation, esterification, amidification, etc., to produce Louis) in animal models, and studies in humans have also structural analogs of the compound, which can be tested for been conducted. The modulation of activation of the NK biological activity (e.g., binding to the NK receptor or receptor, for example, by inhibiting NK's endogenous ligand changes in intracellular calcium concentration as a result of (s) (e.g., NKA) from binding to its receptor, can diminish or receptor activity) using methods described herein or other eliminate disorders or diseases associated with NK receptor methods known to one skilled in the art. activity. 0171 Another way to obtain functional analogs of the 0.175. A compound having the structure depicted by For compound of Formula (I) is through rational design. This is mula (I) has been isolated from the fertilized egg isolate as achieved through structural information and computer mod described herein and has the capacity to displace the neu eling. Prediction of target molecule-compound interaction rotransmitter neurokinin A (NKA) from its human NK when Small changes are made in one or both can be done receptor. The compound of Formula (I) has also been synthe using molecular modeling software and computationally sized and found to displace the neurotransmitter neurokinin A intensive computers. Examples of molecular modeling sys (NKA) from the human NK receptor and alter downstream tems are the CHARMm and QUANTA programs. Accelrys intracellular calcium levels. Accordingly, a compound of For Inc., San Diego, Calif. CHARMm performs the energy mini mula (1), Formula (I), as well as functional analogs and mization and molecular dynamics functions. QUANTA per pharmaceutically acceptable salts thereof can be used to treat forms the construction, graphic modeling and analysis of disorders or diseases associated with NK receptor activity. molecular structure. QUANTA allows interactive construc 0176 Accordingly, another aspect of the invention fea tion, modification, visualization, and analysis of the behavior tures a method for treating a disorder or disease associated of molecules with each other. Other computer programs that with NK receptor activity using a compound of Formula (1). screen and graphically depict chemicals are known to those Formula (I) or a functional analog or pharmaceutically skilled in the art. Functional analogs obtained through ratio acceptable salt thereof, the method comprising the step of nal drug design can also be tested for biological activity (e.g., administering a therapeutically effective amount of the com binding to the NK receptor or changes in intracellular cal pound of Formula (1), Formula (I) or a functional analog or cium concentration as a result of receptor activity) using pharmaceutically acceptable salt thereof to a patient in need methods described herein or other methods known to one thereof. The disorder or disease associated with NK receptor skilled in the art. activity can be, for example, a depressive mood disorder, Such as major depressive disorder, anxiety, inflammatory bowel Therapeutic Uses for the Compounds of the Invention: disease, irritable bowel syndrome, inflammatory airway dis (0172. As described in PCT publication number WO 2009/ ease or urinary incontinence. 086634, the entire teachings of which are incorporated herein 0177. As will be appreciated by one skilled in the art, a by reference, fertilized egg isolate can be used to treat patients compound of Formula (1), Formula (I) or a functional analog Suffering from mental health disorders, including depressive or pharmaceutically acceptable salt thereof can be used to mood disorders, such as major depressive disorder, dysthy treat disorders or conditions with which depression is asso US 2012/O 190743 A1 Jul. 26, 2012

ciated, such as disorders of the brain or nervous system, tion to a patient, including Suspensions (e.g., aqueous or Substance abuse, eating disorders and hormone disorders, non-aqueous liquid Suspensions, oil-in-water emulsions, or a Such as thyroid dysfunction, hypogonadism, menopause, etc. water-in-oil liquid emulsions), solutions and elixirs. In addition, such a compound or analog or pharmaceutically 0183 The composition, shape, and type of dosage forms acceptable salt thereof can be used to treat other conditions for which antidepressants have been demonstrated to be of the invention will typically vary depending on their use. effective, such as hot flashes associated with menopause, pain For example, a dosage form suitable for mucosal administra and Smoking cessation. tion may containa Smalleramount of active ingredient(s) than 0178. In the methods for treating a disorder or disease or an oral dosage form used to treat the same indication. This condition associated with NK receptor activity, the patient aspect of the invention will be readily apparent to those may or may not be being treated by psychotherapy concur skilled in the art. See, e.g., Remington's Pharmaceutical Sci rently with the treatment. ences (1990) 18th ed., Mack Publishing, Easton, Pa. 0179 The compounds of the present invention can be for 0.184 Typical pharmaceutical compositions and dosage mulated for and administered as various dosage forms. Such forms comprise one or more excipients. Suitable excipients as those adapted for administration by the oral (including are well known to those skilled in the art of pharmacy and/or buccal, Sublingual and by oral inhalation), nasal, topical (in formulation chemistry, and non-limiting examples of suitable cluding buccal, Sublingual and transdermal), or parenteral excipients are provided herein. Whether aparticular excipient (including Subcutaneous, intramuscular, intravenous or intra is Suitable for incorporation into a pharmaceutical composi dermal) routes. Particularly preferred are dosage forms tion or dosage form depends on a variety of factors well adapted for administration by the oral route. Other preferred known in the art including, but not limited to, the way in dosage forms include those adapted for administration by the which the dosage form will be administered to a patient. For vaginal or rectal route, such as a Suppository. example, oral dosage forms such as tablets may contain excipients not Suited for use in parenteral dosage forms. Pharmaceutical Compositions: 0185. The invention further encompasses pharmaceutical 0180. The present invention provides compositions for the compositions and dosage forms that comprise one or more treatment of a disorder or disease associated with NK recep compounds that reduce the rate by which an active ingredient tor activity, Such as a depressive mood disorder (e.g., major will decompose. Such compounds, which are referred to depressive disorder), anxiety disorder, irritable bowel syn herein as “stabilizers' include, but are not limited to, antioxi drome, inflammatory bowel disease, inflammatory airway dants such as ascorbic acid, pH buffers or salt buffers. disease or urinary incontinence. In one embodiment, the com position comprises one or more compounds of the invention, Oral Dosage Forms: or a pharmaceutically acceptable salt thereof. In another embodiment, a composition of the invention comprises one or 0186 Pharmaceutical compositions of the invention that more compounds of the invention, or a pharmaceutically are Suitable for oral administration can be presented as dis acceptable salt thereof, and one or more other prophylactic or crete dosage forms, such as, but not limited to, tablets (e.g., therapeutic agents. In another embodiment, the composition chewable tablets), caplets, capsules and liquids (e.g., flavored comprises a compound of the invention, or a pharmaceuti syrups). Such dosage forms contain predetermined amounts cally acceptable salt thereof, and a pharmaceutically accept of active ingredients, and may be prepared by methods of able carrier, diluent or excipient. In another embodiment, the pharmacy well known to those skilled in the art. Seegener composition is formulated such that it crosses the blood brain ally, Remington's Pharmaceutical Sciences (1990) 18th ed., barrier. Mack Publishing, Easton, Pa. 0181. A composition of the present invention can be a 0187. Typical oral dosage forms of the invention are pre pharmaceutical composition or a single unit dosage form. pared by combining the active ingredient(s) in an admixture Pharmaceutical compositions and dosage forms of the inven with at least one excipient according to conventional pharma tion comprise one or more active ingredients in relative ceutical compounding techniques. Excipients can take a wide amounts and formulated in Such a way that a given pharma variety of forms depending on the form of preparation desired ceutical composition or dosage form can be used to treat a for administration. For example, excipients Suitable for use in disorder or disease associated with NK receptor activity. oral liquid or aerosol dosage forms include, but are not limited Preferred pharmaceutical compositions and dosage forms to, water, glycols, oils, alcohols, flavoring agents, preserva comprise a compound of Formula (1), Formula (I) or a func tives and coloring agents. Examples of excipients suitable for tional analog or pharmaceutically acceptable salt thereof, use in Solid oral dosage forms (e.g., powders, tablets, capsules optionally in combination with one or more additional active and caplets) include, but are not limited to, starches, Sugars, agents. micro-crystalline cellulose, diluents, granulating agents, 0182 Single unit dosage forms of the invention are suit lubricants, binders and disintegrating agents. able for oral, mucosal (e.g., nasal, Sublingual, vaginal, buccal 0188 Because of their ease of administration, tablets and or rectal), parenteral (e.g., Subcutaneous, intravenous, bolus capsules represent the most advantageous oral dosage unit injection, intramuscular or intraarterial), or transdermal forms, in which case solid excipients are employed. If administration to a patient. Examples of dosage forms desired, tablets can be coated by standard aqueous or non include, but are not limited to: tablets; caplets; capsules. Such aqueous techniques. Such dosage forms can be prepared by as soft elastic gelatin capsules; cachets; troches; lozenges; any of the methods of pharmacy. In general, pharmaceutical dispersions; Suppositories; ointments; cataplasms (poul compositions and dosage forms are prepared by uniformly tices); pastes; powders; dressings; creams; plasters; Solu and intimately admixing the active ingredients with liquid tions; patches; aerosols (e.g., nasal sprays or inhalers); gels; carriers, finely divided solid carriers, or both, and then shap liquid dosage forms suitable for oral or mucosal administra ing the product into the desired presentation if necessary. US 2012/O 190743 A1 Jul. 26, 2012

0189 For example, a tablet can be prepared by compres oil, light mineral oil, glycerin, Sorbitol, mannitol, polyethyl sion or molding. Compressed tablets can be prepared by ene glycol, other glycols, Stearic acid, Sodium lauryl Sulfate, compressing in a Suitable machine the active ingredients in a talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed free-flowing form Such as powder or granules, optionally oil, Sunflower oil, Sesame oil, olive oil, corn oil or soybean mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered oil), Zinc Stearate, ethyl oleate, ethyl laureate, agar, and mix compound moistened with an inert liquid diluent. tures thereof. Additional lubricants include, for example, a 0190. Examples of excipients that can be used in oral syloid silica gel (AEROSIL 200, manufactured by W. R. dosage forms of the invention include, but are not limited to, Grace Co. of Baltimore, Md.), a coagulated aerosol of syn binders, fillers, disintegrants and lubricants. Binders suitable thetic silica (marketed by Degussa Co. of Piano, Tex.), CAB for use in pharmaceutical compositions and dosage forms O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. include, but are not limited to, corn starch, potato starch, or of Boston, Mass.), and mixtures thereof. If used at all, lubri other starches, gelatin, natural and synthetic gums such as cants are typically used in an amount of less than about 1 acacia, Sodium alginate, alginic acid, other alginates, pow weight percent of the pharmaceutical compositions or dosage dered tragacanth, guar gum, cellulose and its derivatives (e.g., forms into which they are incorporated. ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, Sodium carboxymethyl cellulose), polyvinyl pyr rolidone, methyl cellulose, pre-gelatinized starch, hydrox Controlled Release Dosage Forms: ypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), 0.196 Active ingredients of the invention can be adminis microcrystalline cellulose, and mixtures thereof. tered by controlled release means or by delivery devices that 0191 Suitable forms of microcrystalline cellulose are well known to those of ordinary skill in the art. Examples include, but are not limited to, the materials sold as AVICEL include, but are not limited to, those described in U.S. Pat. PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH 105 (available from FMC Corporation, American Viscose Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008, Division, Avicel Sales, Marcus Hook, Pa.), and mixtures 719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, thereof. One specific binder is a mixture of microcrystalline 5,639,476, 5,354,556, and 5,733,566, the entire teaching of cellulose and sodium carboxymethyl cellulose sold as each of which are incorporated herein by reference. Such AVICEL RC-581. Suitable anhydrous or low moisture dosage forms can be used to provide slow or controlled excipients or additives include AVICEL-PH-103J and Starch release of one or more active ingredients using, for example, 15OOLM. hydropropylmethyl cellulose, other polymer matrices, gels, 0.192 Examples of fillers suitable for use in the pharma permeable membranes, osmotic systems, multilayer coat ceutical compositions and dosage forms disclosed herein ings, microparticles, liposomes, microspheres, or a combina include, but are not limited to, talc, calcium carbonate (e.g., tion thereof to provide the desired release profile in varying granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, Sorbitol, proportions. Suitable controlled-release formulations known starch, pre-gelatinized starch, and mixtures thereof. The to those of ordinary skill in the art, including those described binder or filler in pharmaceutical compositions of the inven herein, can be readily selected for use with a compound of the tion is typically present in from about 50 to about 99 weight invention. The invention thus encompasses single unit dosage percent of the pharmaceutical composition or dosage form. forms suitable for oral administration such as, but not limited 0193 Disintegrants are used in the compositions of the to, tablets, capsules, gelcaps and caplets that are adapted for invention to provide tablets that disintegrate when exposed to controlled-release. an aqueous environment. Tablets that contain too much dis 0.197 All controlled-release pharmaceutical products integrant may disintegrate in Storage, while those that contain have a common goal of improving drug therapy over that too little may not disintegrate at a desired rate or under the achieved by their non-controlled counterparts. Ideally, the use desired conditions. Thus, a Sufficient amount of disintegrant of an optimally designed controlled-release preparation in that is neither too much nor too little to detrimentally alter the medical treatment is characterized by a minimum of drug release of the active ingredients should be used to form solid Substance being employed to cure or control the condition in oral dosage forms of the invention. The amount of disinte a minimum amount of time. Advantages of controlled-release grant used varies based upon the type of formulation, and is formulations include extended activity of the drug, reduced readily discernible to those of ordinary skill in the art. Typical dosage frequency and increased patient compliance. pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from 0198 Most controlled-release formulations are designed about 1 to about 5 weight percent of disintegrant. to initially release an amount of drug (active ingredient) that 0194 Disintegrants that can be used in pharmaceutical promptly produces the desired therapeutic effect, and gradu compositions and dosage forms of the invention include, but ally and continually releases other amounts of drug to main are not limited to, agar-agar, alginic acid, calcium carbonate, tain this level of therapeutic or prophylactic effect over an microcrystalline cellulose, croScarmellose sodium, crospovi extended period of time. In order to maintain this constant done, polacrilin potassium, sodium starch glycolate, potato or level of drug in the body, the drug must be released from the tapioca starch, other starches, pre-gelatinized Starch, other dosage form at a rate that will replace the amount of drug starches, clays, otheralgins, other celluloses, gums, and mix being metabolized and excreted from the body. Controlled tures thereof. release of an active ingredient can be stimulated by various 0.195 Lubricants that can be used in pharmaceutical com conditions including, but not limited to, pH, temperature, positions and dosage forms of the invention include, but are enzymes, water, or other physiological conditions or com not limited to, calcium Stearate, magnesium Stearate, mineral pounds. US 2012/O 190743 A1 Jul. 26, 2012

Parenteral Dosage Forms: improve delivery of one or more active ingredients. Similarly, 0199 Parenteral dosage forms can be administered to the polarity of a solvent carrier, its ionic strength or tonicity patients by various routes including, but not limited to, Sub can be adjusted to improve delivery. Compounds such as cutaneous, intravenous (including bolus injection), intramus Stearates can also be added to pharmaceutical compositions cular and intraarterial. Because their administration typically or dosage forms to advantageously alter the hydrophilicity or bypasses patients natural defenses against contaminants, lipophilicity of one or more active ingredients so as to parenteral dosage forms are preferably sterile or capable of improve delivery. In this regard, Stearates can serve as a lipid being sterilized prior to administration to a patient. Examples vehicle for the formulation, as an emulsifying agent or Sur of parenteral dosage forms include, but are not limited to, factant, and as a delivery-enhancing or penetration-enhanc Solutions ready for injection, dry products ready to be dis ing agent. Different salts, hydrates or Solvates of the active Solved or Suspended in a pharmaceutically acceptable vehicle ingredients can be used to further adjust the properties of the for injection, Suspensions ready for injection and emulsions. resulting composition. 0200 Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to Dosage & Frequency of Administration: those skilled in the art. Examples include, but are not limited 0205 The amount of a compound or composition of the to: Water for Injection USP; aqueous vehicles such as, but not invention which will be effective in the treatmentofa disorder limited to, Sodium Chloride Injection, Ringer's Injection, or disease associated with NK receptor activity, or one or Dextrose Injection, Dextrose and Sodium Chloride Injection, more symptoms thereof, will vary with the nature and severity and Lactated Ringer's Injection; water-miscible vehicles of the disorder or disease, and the route by which the active Such as, but not limited to, ethyl alcohol, polyethylene glycol, ingredient is administered. The frequency and dosage will and polypropylene glycol; and non-aqueous vehicles such as, also vary according to factors specific for each patient but not limited to, corn oil, cottonseed oil, peanut oil, Sesame depending on the specific therapy (e.g., therapeutic or pro oil, ethyl oleate, isopropyl myristate and benzyl benzoate. phylactic agents) administered, the severity of the disorder, 0201 Compounds that increase the solubility of one or disease, or condition, the route of administration, as well as more of the active ingredients disclosed herein can also be age, body, weight, response, and the past medical history of incorporated into the parenteral dosage forms of the inven the patient. Effective doses may be extrapolated from dose tion. response curves derived from in vitro or animal model test systems. Suitable regiments can be selected by one skilled in Transdermal, Topical and Mucosal Dosage Forms: the art by considering such factors and by following, for 0202 Transdermal, topical and mucosal dosage forms of example, dosages reported in the literature and recommended the invention include, but are not limited to, ophthalmic solu in the Physician's Desk Reference (62nd ed., 2008). tions, sprays, aerosols, creams, lotions, ointments, gels, solu 0206. In general, the recommended daily dose range of a tions, emulsions, Suspensions or other forms known to one of compound of the invention for the disorders or diseases skill in the art. See, e.g., Remington's Pharmaceutical Sci described herein lie within the range of from about 0.01 mg to ences (1980 & 1990) 16th and 18th eds., Mack Publishing, about 2000 mg per day, given as a single once-a-day dose or Easton, Pa. and Introduction to Pharmaceutical Dosage as divided doses throughout a day. In one embodiment, the Forms (1985) 4th ed., Lea & Febiger, Philadelphia, Pa. Dos daily dose is administered twice daily in equally divided age forms Suitable for treating mucosal tissues within the oral doses. Preferably, a daily dose range is from about 5 mg to cavity can be formulated as mouthwashes or as oral gels. about 1000 mg per day, more specifically, between about 10 Further, transdermal dosage forms include “reservoir type' or mg and about 500 mg per day. In managing the patient, the “matrix type' patches, which can be applied to the skin and therapy should be initiated at a lower dose, perhaps about 1 worn for a specific period of time to permit the penetration of mg to about 25 mg, and increased if necessary up to about 200 a desired amount of active ingredients. mg to about 1000 mg per day as either a single dose or divided 0203 Suitable excipients (e.g., carriers and diluents) and doses, depending on the patient’s global response. It may be other materials that can be used to provide transdermal, topi necessary to use dosages of the active ingredient outside the cal and mucosal dosage forms encompassed by this invention ranges disclosed herein in some cases, as will be apparent to are well known to those skilled in the pharmaceutical arts, and those of ordinary skill in the art. Furthermore, it is noted that depend on the particular tissue to which a given pharmaceu the clinician or treating physician will know how and when to tical composition or dosage form will be applied. With that interrupt, adjust or terminate therapy in conjunction with fact in mind, typical excipients include, but are not limited to, individual patient response. water, acetone, ethanol, ethylene glycol, propylene glycol, 0207 Prophylactic or therapeutic agents other than com butane-1,3-diol, isopropyl myristate, isopropyl palmitate, pounds of the invention, which have been or are currently mineral oil, and mixtures thereof to form lotions, tinctures, being used to treat a disorder or disease associated with NK creams, emulsions, gels or ointments, which are non-toxic receptor activity, or one or more symptoms thereof can be and pharmaceutically acceptable. Moisturizers or humectants used in the combination therapies of the invention. For can also be added to pharmaceutical compositions and dosage example, the compounds of the invention can be formulated forms if desired. Examples of such additional ingredients are with other antidepressants such as those that may inhibit the well known in the art. See, e.g., Remington's Pharmaceutical breakdown of serotonin, Such as monoamine oxidase inhibi Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, tors. In one embodiment, the additional therapeutic agent is Easton, Pa. one that binds to a glutamate receptor, for example, the 0204 The pH of a pharmaceutical composition or dosage AMPA receptor, the kainate receptor, the agonist site of the form, or of the tissue to which the pharmaceutical composi NMDA receptor or the glycine site that is strychnine-insen tion or dosage form is applied, may also be adjusted to sitive of the NMDA receptor. US 2012/O 190743 A1 Jul. 26, 2012

0208 Examples of useful therapeutic agents for treating or 0214) Examples of useful therapeutic agents for treating or preventing depression include, but are not limited to, tricyclic preventing inflammatory airway disease include, but are not antidepressants such as amitriptyline, amoxapine, bupropion, limited to, anti-inflammatory agents, such as corticosteroids; clomipramine, desipramine, doxepin, imipramine, mapro leukotriene modifiers; mast cell stabilizers; and bronchodila tiline, nefazadone, nortriptyline, protriptyline, traZodone, tors such as beta-adrenergic agonists, drugs with anticholin trimipramine and Venlafaxine; selective serotonin reuptake ergic effects, and methylxanthines. inhibitors such as fluoxetine, fluvoxamine, paroxetine and Sertraline; monoamine oxidase inhibitors such as isocarbox 0215 Preferably, dosages lower than those which have azid, pargyline, pheneizine and tranylcypromine; and psy been or are currently being used to treat a disorder or disease chostimulants such as dextroamphetamine and methylpheni associated with NK receptor activity, or one or more symp date. toms thereof, are used in the combination therapies of the 0209. Other examples of useful antidepressants include, invention. The recommended dosages of agents currently but are not limited to, binedaline, caroXaZone, citalopram, used for the prevention, treatment, management, or amelio dimethazan, fencamine, indalpine, indeloxazine hydro ration of a disorder or disease associated with NK receptor choloride, nefopam, nomifensine, oxitriptan, oxypertine, thi activity, or one or more symptoms thereof, can be obtained aZesim, benmoxine, iproclozide, iproniazid, nialamide, octa from any reference in the art including, but not limited to, moxin, phenelzine, cotinine, rolicyprine, rolipram, Hardman et al., eds., 1996, Goodman & Gilman's The Phar metralindole, mianserin, mirtazepine, adinazolam, amitrip macological Basis Of Basis Of Therapeutics 9. Sup.th Ed. tylinoxide, butriptyline, demexiptiline, dibenzepin, dimeta McGraw-Hill, New York: Physician's Desk Reference (PDR) crine, dothiepin, fluacizine, imipramine N-oxide, iprindole, 62nd Ed., 2008, Medical Economics Co., Inc., Montvale, lofepramine, melitracen, metapramine, noxiptilin, N.J., which are incorporated herein by reference in their opipramol, pizotyline, propizepine, quinupramine, tianept entirety. ine, adrafinil, benactyzine, butacetin, dioxadrol, dulloxetine, 0216. In certain embodiments, when the compounds of the etoperidone, febarbamate, femoxetine, fenpentadiol. invention are administered in combination with another hematoporphyrin, hypericin, levophacetoperane, medifoX therapy, the therapies (e.g., prophylactic or therapeutic amine, milnacipran, minaprine, moclobemide, nefazodone, agents) are administered simultaneously or separately, for oxafloZane, piberaline, prolintane, pyriSuccideanol, example, less than 30 minutes, 1 hour, 3 hours, 5 hours, 10 ritanserin, roXindole, rubidium chloride, Sulpiride, tan hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours apart, dospirone, thozalinone, tofenacin, toloXatone, L-tryptophan, or 72 hours apart. Viloxazine and Zimelidine. 0217. Another aspect of the invention features a method 0210 Examples of useful therapeutic agents for treating or for modulating an activity of an NK receptor comprising preventing anxiety disorder include, but are not limited to, contacting the NK receptor with an effective amount of a benzodiazepines, such as alprazolam, brotizolam, chlordiaz compound of the present invention. epoxide, clobazam, clonazepam, cloraZepate, demoXepam, 0218. The activity of an NK receptor can be modulated by diazepam, estazolam, flumazenil, flurazepam, halazepam, increasing or decreasing (i.e., inhibiting) the activity of the lorazepam, midazolamn, nitrazepam, nordazepam, oxazepam, praZepam, quaZepam, temazepam and triazolam: NK receptor. The activity of the NK receptor can be non-benzodiazepine agents, such as buspirone, gepirone, decreased or inhibited, for example, by inhibiting binding of ipsapirone, tioSpirone, Zolpicone, Zolpidem and Zaleplon; the receptor by its endogenous ligand(s) (e.g., NKA for the tranquilizers, such as barbituates, e.g., amobarbital, aprobar NK receptor), or by commercially available exogenous bital, butabarbital, butalbital, mephobarbital, methohexital, ligands. Such as Saredutant. Methods for inhibiting Such bind pentobarbital, phenobarbital, secobarbital and thiopental; ing interactions and for detecting Such binding inhibition are and propanediol carbamates. Such as meprobamate and known to those skilled in the art, and are also described tybamate. herein. Activity of the NK receptor can be decreased by 0211 Examples of useful therapeutic agents for treating or 100% or by less than 100% (for example, by 90%, 80%, 70%, preventing inflammatory bowel disease include, but are not 60%, 50%, 40%, 30%, 20% or 10%). Inhibition of NK, limited to, anticholinergic drugs, diphenoxylate, loperamide, receptor activity can occur, for example, by the compound of deodorized opium tincture, codeine; broad-spectrum antibi Formula (1) or Formula (I) binding to the endogenous ligand otics such as metronidazole, Sulfasalazine, olsalazine, binding site, thereby decreasing binding by the endogenous mesalamine, prednisone, azathioprine, mercaptopurine and ligand. Inhibition of NK receptor activity can also occur but methotrexate. the binding of the compound of Formula (1) or Formula (I) to 0212. Examples of useful therapeutic agents for treating or a site on the NK receptor that is different than the endog preventing irritable bowel syndrome include, but are not lim enous ligand binding site, yet alters (e.g., decreases) the activ ited to, propantheline; muscarine receptorantogonists such as ity of the NK receptor upon interaction with its endogenous pirenzapine, methoctramine, ipratropium, tiotropium, Scopo ligand (e.g., allosteric modification of the receptor). Activity lamine, methScopolamine, homatropine, homatropine meth of the NK receptor can be increased by 5% or by more than ylbromide and methantheline; and antidiarrheal drugs such as 5% (for example, by 10%, 20%, 30%, 40%, 50%, 60%, 70%, diphenoxylate and loperamide. 80% or 90%, 100% or more than 100%). Methods for modu 0213 Examples of useful therapeutic agents for treating or lating the activity of an NK receptor can be carried out in preventing urinary incontinence include, but are not limited vitro (for example, in a cell, cell lysate, or a sample containing to, propantheline, imipramine, hyoscyamine, oxybutynin and a portion of a cell, for example, just the relevant receptor) or dicyclomine. in vivo (for example, in a human patient). US 2012/O 190743 A1 Jul. 26, 2012

Other Embodiments 0226 Formulation A Capsules 0219. The compounds of the invention may be used as 0227. In order to prepare capsules of Formulation A, research tools (for example, to evaluate the mechanism of 4000.0 g (+/-2%) of the finished powder containing Isolate A, action of new drug agents, to isolate new drug discovery sodium benzoate (0.5% w/w) and potassium sorbate (0.2% targets using affinity chromatography, as antigens in an w/w) was mixed with 40 g (+/-2%) of fumed silica using ELISA or ELISA-like assay, or as standards in in vitro or in geometric dilution. The mixture was sifted, and the mixing Vivo assays). These and other uses and embodiments of the and sifting were repeated, resulting in Formulation A. The compounds and compositions of this invention will be appar Formulation A mixture was encapsulated using Mini-Cap ent to those of ordinary skill in the art. 300#0 white capsules to a target fill weight of 505 mg to 0220. The invention is further defined by reference to the produce Formulation A capsules. following examples describing in detail the preparation of compounds of the invention. It will be apparent to those Example 2 skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the Study of Formulation A for Treatment of Major purpose and interest of this invention. The following Depressive Disorder (MDD) and Disorders/Symp examples are set forth to assist in understanding the invention toms Related Thereto and should not be construed as specifically limiting the inven tion described and claimed herein. Such variations of the 0228. The efficacy and safety of a fixed dose of Formula invention, including the Substitution of all equivalents now tion A to treat mental disorders, such as MDD and related known or later developed, which would be within the purview disorders and symptoms, were studied. This study included of those skilled in the art, and changes informulation or minor evaluation of the effect of Formulation A on reducing symp changes in experimental design, are to be considered to fall toms of anxiety, improving quality of life, and improving within the scope of the invention incorporated herein. symptoms of sexual dysfunction. EXAMPLES 0229 Description of Evaluation Techniques 0230 Hamilton Depression Rating Scale-17 Item— Example 1 HAM-D. Or HAM-D 17 0231. This is a leading rating scale used in North America Preparation of Fertilized Egg Isolate A for evaluating depression in a patient. The total scores are 0221) To produce fertilized egg Isolate A, 8-9 day old interpreted as follows: very severe, >23; severe, 19-22; mod whole fertilized hen eggs were disinfected with 70% ethanol erate, 14-18; mild, 8-13; and no depression, 0-7. and left in a fume hood to allow the solvent to evaporate. The 0232 Hamilton Anxiety Rating Scale-14 Item “HAM eggs were thenbroken and the contents dropped on orthrough A. a sterile 1.0 mm mesh. The shells and filtrate were discarded. 0233. This rating scale evaluates the level of anxiety in a The retentate, which comprised the embryo, clear sac, and all patient. The score levels are interpreted as follows: <17, mild: or a Substantial part of the albumen and consisted of solid and 18-24, mild to moderate; and 25-30, moderate to severe. semi-solid and/or liquid portions, was chilled on ice and then 0234) Montgomery-Asberg Depression Rating Scale— homogenized at 5° C. The homogenate (slurry) was poured “MADRS into sterile stainless steel trays, and freeze-dried. The dried product was pulverized in a grinder to give Isolate A. To 0235. This is a leading rating scale used in North America Isolate A, the preservatives sodium benzoate (0.5% w/w) and for evaluating depression in a patient. The following mean potassium sorbate (0.2% w/w) were added and the mixture scores correlate with global severity measures, according to a was blended. The finished powder was stored at 2-8°C. (short study: very severe, 44; severe, 31; moderate, 25; mild, 15; and term) or -20°C. (long term). recovered, 7. 0222 HPLC Analysis 0236 Beck Depression Inventory “BDI’ 0223) The finished powder containing fertilized egg Iso 0237. This is a commonly employed measure of depres late A was analyzed by High Performance (or Pressure) Liq sive symptoms typically used as a self-assessment instru uid Chromatography (HPLC). The results were quantified ment. The total score is the simple sum of the 21 item scores. using a multiple-wave absorption detector. Absorption was Generally, a score<9 indicates no or minimal depression, read at 215 nm. A Pharmacia Superdex 200 10/300GL size 10-18 indicates mild-to-moderate depression, 19-29 indi exclusion column (10 mm i.d.x300mm) was used for frac cates moderate-to-severe depression, and >30 indicates tionation. The separation range of the column was 10 kDa severe depression. However, a score of 0-4 may suggest pos 600 kDa. The column was equilibrated with 20 mM phos sible denial of depression and a score of 40-63 may suggest phate--0.3 MNaCl, pH 7.5. The sample was analyzed at a flow possible exaggeration of depression or a histrionic or border rate of 0.5 mL/min. A representative chromatogram is shown line personality disorder. at FIG. 1. 0238 Arizona Sexual Experience Scale ASEX” 0224 Certificate of Analysis 0239. This is a 5-item rating scale that quantifies sex drive 0225. The finished powder containing Isolate A was also and evaluates levels of arousal, vaginal lubrication/penile Subjected to standard analytical procedures to measure purity erection, ability to reach orgasm, and satisfaction from and the content of protein, fat, ash, moisture, and various Orgasm. contaminants. A representative sample of the results is shown 0240 Possible total scores range from 5 to 30, with the at FIG. 2. higher scores indicating more sexual dysfunction. US 2012/O 190743 A1 Jul. 26, 2012 20

0241 General Health Questionnaire Scoring “GHQ 0258 Inclusion Criteria of Patients 0242. The quality of life dimension may be assessed with 0259 For inclusion in this study, patients had to have met the Short-Form 36 (SF-36). This questionnaire evaluates such a number of inclusion criteria, including criteria (i)-(vi), as problems as the ability to concentrate, feelings of worry, low described below. self-confidence, feelings of low self-worth, unhappiness, and 0260 (i) A clinical diagnosis fulfilling DSM-IV TR crite depression. The scoring is as follows: ria for major depressive disorder, single episode or recurrent. 0243 Likert Scale 0, 1, 2, 3 from left to right; 12 items 0261 (ii) 17-Item Hamilton Depression Rating Scale were assessed on a scale of 0 to 3 for each item. (HAM-D 17-item) total score at baseline of 18 or higher. 0244 Score Range 0 to 36. 0262 (iii) Males/Females 18-65 years of age who require a new or a change in their medication treatment for diagnosed 0245 Scores vary by study of population. Scores about major depression. Treatment decisions were made solely 11-12 are typical. upon the clinician's judgment of the standard of care appro 0246 Scored 15 evidence of distress. priate to that patient. However augmentation strategies were 0247 Score-20 suggests severe problems and psycho not permitted during the 8 week trial. logical stress. 0263 (iv) English language literacy. 0248 Diagnostic and Statistical Manual of Mental Disor 0264 (v) Signed written informed consent obtained. ders-IV-Text Revision “DSM-IV TR 0265 (vi) A negative pregnancy test at Screening. 0249. This is the standard diagnostic manual in North 0266 Exclusion Criteria America for mental health professionals that comprehen 0267 Patients were excluded from this study if they met a sively classifies mental disorders and provides widely number of exclusion criteria, including criteria (i)-(xiii), as accepted criteria for diagnosing them based on the best described below. empirical evidence available. 0268 (i) Any other DSM IV TR diagnosis including a 0250. The primary effect measured was the repeated clinical diagnosis of depression other than DSM-IV TRMDD analysis of variance with the score on the HAM-D as the (single episode/recurrent, e.g., chronic depression and/or outcome variable. Secondary effect measures included the refractory depression were excluded). CGI-S and CGI-I, MADRS, SF36, BDI, HAMA and ASEX. 0269 (ii) Judged to be at significant risk for suicide 0251. Description of Study (HAMD suicide item-1) or having a history suggesting sig 0252) An open-label study was carried out at Mount Sinai nificant current potential for self harm. Hospital (MSH) in Toronto, Ontario, Canada. Patients were 0270 (iii) Any antidepressant medication other than For recruited by media advertisement, referral from the MSH mulation A. outpatient program and from other clinical centers. 0271 (iv) Subjects who were taking and unable or unwill 0253) This protocol describes an open pilot study to inves ing to discontinue natural health products used for depres tigate Formulation A's potential antidepressant activity. The Sion. goal of the pilot study was to demonstrate that Formulation A 0272 (v) Women who were pregnant, breast-feeding, has the potential to significantly improve MDD beyond the intending to become pregnant in the next 12 months or on levels of the known placebo effect well established in other insufficient contraceptive protection. trials and that Formulation A is an acceptable treatment in this 0273 (vi) Clinically significant organ system diseases, patient population. Secondary aims of this pilot study were to e.g., cardiovascular, hepatic, renal, endocrine, gastrointesti evaluate the effect of FormulationA on reducing symptoms of nal, metabolic, or other systemic diseases. anxiety and improving quality of life. 0274 (vii) Course of electroconvulsive therapy (ECT) 0254 Each patient was screened for MDD using DSM-IV during the observational period. TR criteria and the HAM-D. Once entered, they were 0275 (viii) Suffer from a major neurological condition assigned to the open-label Formulation Astudy for a period of (i.e., Parkinson's disease, Huntington's disease), cerebrovas 8 weeks. The patients were further assessed by a global mea cular disease (i.e., stroke), metabolic conditions (i.e., Vitamin sure, the CGI severity (GCI-S) and improvement (CGI-I) B12 deficiency), autoimmune conditions (i.e., systematic scales. Side effects were systematically evaluated using The lupus erythematosus), viral or other infections (i.e., hepatitis, Udvalg for Kliniske Undersogelser (UKU)Side Effect Rating mononucleosis, human immunodeficiency), or cancer. Scale (Lingjaerde). Secondary measures of depressive symp 0276 (ix) Clinical or subclinical hypo/hyper thyroidism toms were the Montgomery Asberg Depression Rating Scale (e.g., elevated TSH). (MADRS) and the Beck Depression Inventory (BDI) as self 0277 (x) Allergies to poultry or eggs. assessment instruments. The quality of life dimension was 0278 (xi) Subjects who were receiving psychotherapy or assessed with the Short-Form 36 (SF-36). Anxiety was who began psychotherapy during the trial. assessed using the 14 item HAM-A. 0279 (xii) Subjects with clinically significant abnormal 0255. In the fixed dose open trial, patients were treated for laboratory results from screening blood and urinalysis. depression based on standard treatment protocols for depres 0280 (xiii) Subjects who became significantly worse dur Sion. The investigators determined the severity of depression ing the washout period. with the rating scales at baseline, and at repeated visits at (0281 Study Design weeks (W) 2, 4, 6, and at week 8. In intervening weeks 0282. This was a single site, open-label, randomised study patients were seen in brief clinical assessments (V) to evalu of 23 patients (20 of whom had analyzable results) designed ate depression and medication tolerance. to validate the efficacy and safety of Formulation A mono 0256 Dosage of Formulation A therapy. 0257. The dosage of Formulation A was about 2000 0283. The trial consisted of an 8 week evaluation period mg/day (two Formulation A capsules of about 500 mg each, preceded if necessary by a 2 week antidepressant washout taken orally twice a day). period. US 2012/O 190743 A1 Jul. 26, 2012

0284 Screening 0296 Montgomery-Asberg Depression Rating Scale 0285. Once the physician and/or research coordinator (MADRS) (Montgomery) fully informed the subject of the study, the nature of the 0297. Beck Depression Inventory Scale (BDI) (10). treatment, and the other options available to them, and the - Quality of Life (SF-36) (Ware). Subject signed the informed consent document, the physician 0298 Hamilton rating scale for anxiety (HAMA) made the clinical DSM IVTR diagnosis and administered the HAM-D 17. Eligible subjects then had a medical, psychiatric (Hamilton 1959) history and concomitant therapy review followed by a physi 0299 Udvalg for Kliniske Undersogelser (UKU) cal examination. In addition, baseline laboratory tests were (Lingjaerde) (Reporting of Adverse Events) (except at taken by the research coordinator including urine (Routine & V2) Microscopic), CBC differential and platelets, electrolytes, 0300 Medication Compliance (except at V2) bilirubin, BUN, creatinine, TSH, Liver Function Tests, Serum 0301 Study visits were estimated at about one hour with creatinine, and ECG. A pregnancy screen for female patients the exception of the baseline visit which may have taken 2 was obtained by hCG blood test. Pregnant patients and those hours. with clinically significant abnormal laboratory tests were excluded. 0302) If subjects became more depressed while in the study they were evaluated by the principal investigator to 0286 Week 0 determine the best clinical approach. If deemed necessary, (0287 Patients returned for a Baseline visit (Week 0) and Formulation A was stopped in favour of another antidepres were assigned to Formulation A monotherapy by the physi sant treatment. This was a clinical decision made solely on the cian. Patients who were depressed and on a current but inef basis of best practices in the treatment of depression and on fective antidepressant were offered the switch to Formulation A the patient’s best clinical interests. 0288. Following Weeks 0303 General supportive contact with the patients by the physician and the research coordinator was permitted, and the 0289. Following the initial assessment and initiation of contact was generally restricted to answering pertinent ques Formulation A therapy (V1 and V2) the scheduled visits occurred every week for 8 weeks (W2-W8, V3-V6). Those tions about the patient's illness course and treatment. No who were on another antidepressant drug and who chose to formal psychotherapy was permitted. enter the study entered a 1-2 week washout period before 0304 Statistical Methods beginning the 8 week active drug trial. The washout period 0305 The primary effect was tested using a repeated was at the clinical discretion of the physician. During this analysis of variance with the scores of the HAM-D 17 as the time, patients were monitored in a visit one week into the outcome variable. A significant time effect Supports the washout by the psychiatrist and further monitored by phone hypothesis. The total anticipated sample size of 25 patients by the study coordinator mid-week. It is recognized that was large enough to detect changes on the HAM-D 17 as depression may worsen during the washout period. However, follows 0.65 standard deviations (two-tailed one sample P<0. if the prior drug was ineffective or partially ineffective the 05). The reported standard deviations on the HAM-D-17 risks that a 1-2 week delay will significantly induce depres were in the range of 4.5 to 6.5. Therefore, the design of this sive decline in this protocol are not Substantially greater than study had 80% power to detect average changes as Small as usual care as long as Subjects are carefully monitored during 4.3 points on this 52 point scale. As per inclusion criteria, this time and appropriate intervention instituted as necessary. participants each had a HAM-D 17 score of greater than 17. If Formulation A were not to be an effective antidepressant for The Franck criterion for remission was a HAM-D 17 of 9 or a particular patient, the patient may be at risk for undue under. This study used a more conservative and accepted level prolongation of depression. However, depression is a chronic of 7 or under. The effect size of 4.3 was sufficiently sensitive disorder which is generally present for months prior to being to detect clinical improvement from scores greater than 17 to diagnosed or treated so an additional 8 weeks in the presence scores less than 10. Positive outcome was statistically based of careful monitoring together with institution of Formulation on an expected placebo response rate ranging from 30% to A, a potentially effective medication, should not be substan 50% in treatment trials for depression. In this study, a placebo tially different from standard care. Moreover, standard care, response rate of 40% was assumed. Some analysis of as already discussed, is only effective in about 60% of responders and remitters was carried out as appropriate. patients and therefore often requires the same possible reevaluations and drug alterations. 0306 Results 0290. At V2 (may be combined with V1 (WO)) to V6 0307. A total of 23 patients were entered into the study. (W8), the following procedures were performed by the Super Three of the subjects, (#104, #105 and #118) were never vising psychiatrist (PI) and/or the research coordinator: treated and hence, their results were not considered analyZ able. Of the subjects that received at least one dose of For 0291 Weight mulation A, 16 of them completed the 8 week study. The 0292 Height remaining 4 subjects did not complete the 8 week study, but 0293 Vital Signs since they each received at least one dose of Formulation A, 0294 Hamilton Depression Rating Scale (17 item) their results were deemed analyzable. The reasons these 4 (HAM-D 17) (Hamilton 1967). Subjects did not complete the entire study included non-com 0295) Clinical Global Impression (CGI-S, CGI-I) pliance with the medications and/or appointments, impa (Guy) tience with the results, and the Subject leaving the country. US 2012/O 190743 A1 Jul. 26, 2012 22

0308. The results for the 20 subjects who received at least one dose of Formulation A are provided in the below tables. -continued Total Score Sheet for HAM-D Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 0309 Subjec # 107 38 28 28 Subject if 108 2O 18 22 Subject #109 28 23 2O 28 26 Subject #110 28 16 36 14 10 Subject #111 46 40 40 40 32 36 Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 Subject #112 38 16 10 10 2 Subject #113 46 16 18 14 6 Subject #101 2O 4 11 7 3 Subject #114 42 26 38 38 44 Subject #102 19 5 5 2 O Subject #115 32 12 12 10 10 Subject #103 22 7 3 5 O Subject #116 36 42 44 34 46 Subject # 106 21 4 8 10 12 Subject #117 36 22 10 6 Subject #107 22 7 2O Subject #119 38 34 34 18 10 Subject #108 2O 4 19 Subject # 120 32 6 Subject #109 25 6 17 2O 24 Subject # 121 38 14 6 6 4 Subject # 110 21 O 17 8 4 Subject # 122 44 38 22 32 24 Subject # 111 24 2O 19 19 23 23 Subject # 123 30 28 22 14 16 Subject # 112 29 8 5 2 O Subject #113 33 3 9 11 8 Subject #114 29 3 19 22 30 Subject #115 32 8 13 5 6 Total Score Sheet for BDI-21 Subject if 116 19 7 24 17 24 Subject #117 23 1 9 8 0312 Subject #119 23 23 2O 13 10 Subject # 120 23 5 Subject # 121 23 1 8 6 3 Subject # 122 32 22 16 23 16 Subject # 123 24 9 12 10 11 Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 Subject #101 27 25 27 17 10 Subject #102 25 13 6 O 1 Subject #103 26 14 10 8 8 Total Score Sheet for GHQ Subject #106 30 12 7 12 40 0310 Subjec # 107 33 28 26 Subject if 108 32 14 2O Subject #109 29 23 24 2O 25 Subject #110 29 22 24 13 8 Subject #111 32 28 27 33 27 27 Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 Subject #112 37 21 10 9 1 Subject #113 53 23 22 18 3 Subject #101 15 27 14 11 3 Subject #114 S4 40 52 52 59 Subject #102 22 1 3 O O Subject #115 39 13 16 3 4 Subject #103 18 9 13 2 2 Subject #116 38 37 37 42 40 Subject # 106 22 O 10 6 10 Subject #117 24 2O 11 7 Subject #107 27 2 9 Subject #119 35 36 40 24 18 Subject #108 27 9 17 Subject # 120 26 1 Subject #109 25 6 16 17 2O Subject # 121 43 10 4 3 3 Subject # 110 28 3 16 9 8 Subject # 122 55 38 25 46 27 Subject # 111 26 5 2O 21 21 2O Subject # 123 33 34 22 5 10 Subject # 112 30 5 9 4 O Subject #113 34 3 12 5 2 Subject #114 33 25 22 22 28 Subject #115 31 2 7 5 8 Total Score Sheet for HAM-A Subject if 116 32 26 25 25 24 Subject #117 24 4 7 8 0313 Subject #119 31 9 27 2O 8 Subject # 120 23 8 Subject # 121 35 7 1 1 1 Subject # 122 31 23 10 23 15 Subject # 123 26 7 11 4 2 Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 Subject #101 15 9 8 7 3 Subject # 102 13 8 2 O 1 Subject # 103 8 7 2 O 2 Total Score Sheet for MADRS Subject # 106 21 5 5 5 10 Subject # 107 12 7 13 0311 Subject # 108 15 8 11 Subject # 109 17 12 13 18 14 Subject # 110 14 8 9 2 5 Subject # 111 33 29 24 32 23 24 Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 Subject # 112 22 10 4 1 2 Subject # 113 35 22 14 4 3 Subject #101 34 24 28 10 6 Subject #114 24 10 18 21 21 Subject # 102 30 18 10 O 2 Subject # 115 25 10 12 4 5 Subject # 103 28 10 4 2 2 Subject # 116 12 13 15 12 16 Subject # 106 30 14 14 18 24 Subject # 117 21 10 8 7 US 2012/O 190743 A1 Jul. 26, 2012

factors intervened. She began to encounter medical problems -continued (not related to Formulation A) and difficulty at work when she applied for disability insurance. These environmental factors Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 completely overtook her good emotional response to Formu Subject # 119 13 19 15 13 6 lation A. Subject # 120 14 4 0319 Based on the strict criterion of a 50% reduction in Subject # 121 24 9 3 4 2 the HAM-D score, subject #106 would not have been consid Subject # 122 43 31 21 32 22 ered a responder at week 8 because at that time her score was Subject # 123 23 27 14 8 10 12, just short of a 50% drop from her entry score of 21. Throughout the 8 week trial, however, subject #106 did respond with scores of 4 (week 2), 8 (week 4) and 10 (week 6) Total Score Sheet for ASEX In fact, during the study, subject #106 was deemed to be a clinical responder by the PI and was entered into the Exten 0314) sion Study (see Example 3) where scores of 1, 11, 7 and 9 were recorded. After starting the Extension Study, subject #106 was faced with considerable family turmoil which dis rupted her positive response to Formulation A. When this Screen Week O Week 2 Week 4 Visit 7 Week 6 Week 8 turmoil Subsided she continued to maintain responsiveness to Subject #101 2 4 12 13 13 Formulation A. No medication can completely offset the trau Subject #102 21 23 9 19 15 matic effects of environmental circumstances. Formulation A Subject #103 2 2 7 17 13 Subject # 106 O 9 7 7 10 may well have ameliorated the emotional trauma of those Subject #107 5 4 6 circumstances for subject #106. Subject #108 5 1 2 0320 Remission Rate Subject #109 7 5 7 19 19 0321 Not all ever-responders went into remission and not Subject # 110 26 25 28 28 27 Subject # 111 28 28 28 28 28 28 everyone who went into remission remained there until the Subject # 112 1 3 1 11 9 end of the 8 week study. Nine of the 15 ever-responders (60%) Subject #113 28 28 28 28 9 went into remission at Some point during the 8 week study. Subject #114 28 28 28 30 30 Subject #115 9 7 7 11 15 Seven of those nine subjects (77.8%; or 46.7% of all study Subject #116 1 O 1 12 12 participants) who achieved remission remained in remission Subject #117 4 2 8 16 by the end of the 8 week study. Subject #119 30 30 28 30 30 0322 The table below delineates all those study partici Subject # 120 9 5 Subject # 121 8 26 2 22 10 pants who went into remission and all who stayed in remis Subject # 122 26 4 5 30 12 Sion. Checkmarks indicate that the Subject went into remis Subject # 123 22 2O 2O 16 2O sion or had sustained remission, while X marks indicate that the Subject did not go into remission or did not have Sustained 0315 Response Rate and Intensity of Response remission to week 8 of the study. 0316 The following definitions were used to assess each subject's response to treatment with Formulation A. A “responder or “ever-responder is a subject with at least 50% Remission at any Remission Sustained to 8 improvement on the Hamilton Depression Rating Scale Subject time Weeks (HAM-D score) as compared to baseline score at any time 101 M M during the study. A “clinical responder is a Subject meeting 102 M M the “responder criteria who, in the opinion of the Principal 103 M M 106 M X Investigator has a positive clinical outcome. An 'end of study 110 M M responder is a subject meeting response criteria at the end of 112 M M the study (or at last observation). “Remission' is a reduction 113 X X of the HAM-D score to less than 8. 114 X X 115 M M 0317. The above study showed that of the 20 subjects who 117 X X received at least one dose of Formulations A, 15 of them 119 X X (75%) were ever-responders, and 14 of them (70%) were 120 M withdrew 121 M M clinical responders. In addition, among the 16 Subjects who 122 X X completed the 8 week study, the number of ever-responders 123 X X was 13/16 (81.3%) and the number of clinical responders was Never in N in Sustained 12/16 (75%). In addition, of the 16 subjects who completed remission = 9 remission = 7 the study, the overall drop in HAM-D score (including non (60%) (46.7%) responders) was significant at 56.08%. The drop in HAM-D score among the ever-responders who completed the 8 week 0323. In addition, a major secondary outcome, reduction study was higher, at 68.1%, a figure well beyond the minimal in anxiety, was experienced by all of the ever-responders 50% drop rate require for an ever-response. except one. These results show that Formulation A is effective 0318 Note should be made of two subjects whose in the treatment of major depressive disorder and anxiety. response was influenced by environmental circumstances. Furthermore, there were no serious side-effects attributable to Subject #114, who was not included among the clinical the drug. There was no increase in weight, nor was there a responders, was responsive by week 2 when her HAM-D diminution in sexual function in Subjects participating in the score fell by more than 50% on Formulation A; but external study. US 2012/O 190743 A1 Jul. 26, 2012 24

Example 3 0324. The positive efficacy and safety results of the study -continued described in Example 2 necessitated an Extension Study. Ten Subject Subject Subject Subject subjects from the study described in Example 2 were entered Month ti 102 # 106 ii. 110 # 123 into the Extension Study. The Extension Study was open only to those subjects from the study described in Example 2 who Visit 4 7 Visit S 12 were clinical responders at the end of that 8 week study. Visit 6 2 Formulation A was administered as described in Example 1 Visit 7 2 and the subjects in the Extension Study were analyzed on a Visit 8 monthly basis for 10 months. The below table show the Visit 9 HAM-D scores of the subjects in the Extension Study.

Subject Subject Subject Subject Subject Subject Subject Subject Subject Subject Month ti 102 ti 103 # 106 ii. 110 ii. 112 # 113 ii. 115 # 119 ii. 121 # 123

Visit 1 12 8 6 10 11 Visit 2 1 9 2 10 14 Visit 4 11 10 wid 3 14 Visit 4 7 18 10 3 Visit S 9 wid 4 Visit 6 16 wid Visit 7 d 9 Visit 8 6 Visit 9 11 Visit 10 wid = withdrawn from Extension Study

0325 Four of the 10 subjects were withdrawn from the Extension Study due to occurrence of an exclusionary crite -continued rion for continuing in the study. The results of this Extension Study showed that all of the subjects in the study were, by Subject Subject Subject Subject definition, responders to Formulation A. Six of the 10 clinical Month ti 102 # 106 ii. 110 # 123 responders (60%) were in remission at the outset of the Exten Visit 10 sion Study. Eight of the 10 subjects (80%) were in remission Visit 11 at the last date of assessment. Two of the subjects were clini Visit 12 cal responders in the initial 8 week study but had not gone into remission until in the Extension Study. Only one subject 0327. The results of this Second Extension Study show (#113) who entered the Extension Study as a clinical that all of the subjects in the study (with the exception of responder relapsed after entering the Extension Study. subject #106 at visit 5) have remained in remission (i.e., having a HAM-D score of less than 8) throughout the length Example 4 of time they have been enrolled in the ongoing Second Exten 0326. The positive efficacy and safety results of the Exten sion Study. All of the subjects were in remission at the last sion Study described in Example 3 necessitated a Second date of assessment. Extension Study. Four subjects from the Extension Study described in Example 3 were entered into the Second Exten Example 5 sion Study. The Second Extension Study was open to those subjects from the Extension Study who wanted to continue 0328. As described in the above Examples, Formulation A taking Formulation A. Formulation A was administered as has a demonstrated therapeutic action. As described in PCT described in Examples 2 and 3. The Second Extension Study publication number WO 2009/086634, studies have been is scheduled to last for 12 month, and the four subjects conducted to investigate the mechanism of action of Formu enrolled in the study have currently completed either 8 or 9 lation A. In particular, Studies were conducted to determine months of the study. Each subject has been, and will be, inhibition of binding interactions between radioligands and analyzed on a monthly basis. The below table show the their receptors, or inhibition of radio-labeled enzymes to act HAM-D scores of the subjects in the Extension Study. on their associated target proteins by Formulation A. The level of inhibition by Formulation A (measured as percent inhibition of specific binding to each receptor by Formulation A) was determined. The testing of inhibition of binding inter Subject Subject Subject Subject actions and enzymatic activities was performed in duplicate Month ti 102 # 106 ii. 110 # 123 for each sample at two different concentrations of Formula Visit 1 3 1 3 4 tion A (1.0 ug/mL and 10.0 ug/mL). These concentrations of Visit 2 O 3 O 2 Formulation A were prepared by dissolving the contents of a Visit 4 O 4 1 5 capsule of Formulation A in dimethyl sulfoxide and subse quently diluting the solution to either 1.0 ug/mL or 10.0 US 2012/O 190743 A1 Jul. 26, 2012

ug/mL of Formulation A. These diluted solutions were called were each dried down. The bottom (aqueous) fraction was Isolate A. Radioligand binding assays were then performed reconstituted in 2.06 mL of water. The sample was not clear using more than 60 different receptors and enzymes (as and it was centrifuged at 10,000 rpm for ten minutes using a described in detail in PCT publication number WO 2009/ microcentrifuge. The Supernatant was removed, labeled as 086634). The average percent inhibition of specific binding at sample 085426-4 (Sample #19 Bottom Isolate) and used in each concentration of Isolate A was then determined. the receptor binding studies. The top (organic) fraction was 0329. Of the more than 60 receptors and enzymes tested, 5 reconstituted in 1.245 mL of 20% acetonitrile in water. The receptors showed binding inhibition activity. The results of sample was not clear and it was centrifuged at 10,000 rpm for this study showed that binding by neurokinin A to the human ten minutes using a microcentrifuge. The Supernatant was NK receptor was inhibited by 32.15% in the presence of removed, labeled as sample 085426-3 (Sample #19 Top Iso Isolate A (approximately 10 ug/mL). The dissociation con late) and used in the receptor binding studies. A control for stant (K) was 5x10' M and the inhibition constant (K) of sample #19 was also made. This control consisted of 20% the reference compound, neurokininA, was 2.53x10'M. In acetonitrile in water, and was labeled as sample 085426-5 in addition, the above-described binding inhibition studies the receptor binding studies. showed that Isolate A displaced glutamate from four of its 0332 Sample #20 was prepared by weighing out 249.7 mg major ionotropic receptors. Binding by radio-labeled AMPA of the contents of a Formulation A capsule. Ten mL of 1:1 to the AMPA receptor was inhibited by 29.05% in the pres methanol:dichloromethane was added and the Solution was ence of Isolate A (approximately 10 g/mL). Binding by Vortexed. Ten mL of dichloromethane was then added to the radio-labeled kainic acid to the kainate receptor was inhibited Solution and the Solution was Vortexed again. The sample was by 22.38% in the presence of Isolate A (approximately 10 then centrifuged at 3500 rpm for fifteen minutes using a ug/mL). Binding by radio-labeled CGP39653 to the agonist bench-top Beckman centrifuge. Three fractions were formed site of the NMDA receptor was inhibited by 34.59% in the as a result. The top and bottom organic fractions were col presence of Isolate A (approximately 10 ug/mL). Binding by lected separately. The middle fraction was discarded. The top radio-labeled MDL-105,519 to the glycine site that is strych and bottom fractions were each dried down and reconstituted nine-insensitive of the NMDA receptor was inhibited by in 2.49 mL of 100% methanol in water. The top methanol 27.45% in the presence of Isolate A (approximately 10 fraction was semi-clear and the bottom dichloromethane frac Lig/mL). tion was not soluble. Both samples were centrifuged at 10,000 0330. The NK receptor was used in additional receptor rpm for ten minutes using a microcentrifuge. The Supernatant binding assays. A one-concentration controlled experiment of each sample was removed. The Supernatant from the top was performed to assess the ability of various isolates of the methanol fraction was labeled as sample 085426-6 (Sample contents of a Formulation A capsule to antagonize ligand #20 Top Isolate) and used in the receptor binding studies. The binding by the NK receptor. The contents of Formulation A supernatant for the bottom dichloromethane fraction was capsules were dissolved using various solvents and extracted labeled as sample 085426-7 (Sample #20 Bottom Isolate) and using four different processes, as described in detail below. used in the receptor binding studies. A control for sample #20 These extraction procedures resulted in a number of isolates. was also made. This control consisted of 10% methanol in These isolates were called: Sample #19 Top Isolate, Sample water, and was labeled as sample 085426-9 in the receptor #19 Bottom Isolate, Sample #20 Top Isolate, Sample #20 binding studies. Bottom Isolate, Fraction X Isolate and Sample #2 Isolate. 0333 Sample Fraction X was prepared as follows. One These isolates were then each tested in the radioligand bind hundred and twenty-one mg of the contents of a Formulation ing assay. In order to more easily track the binding activity in A capsule was weighed out. Ten mL of water was then added. the assay, higher concentrations of isolate were used (e.g., Ten mL of dichloromethane was then added to the solution approximately 100 ug/ml). This radioligand binding assay and the sample was Vortexed. The aqueous and organic frac was performed based on the methods of Burcher and of tions were each separately removed. The solvent isolation Regoli. In general, Chinese Hamster Ovary (CHO) cells was repeated by adding 10 mL of dichloromethane to the expressing recombinant human NK receptor were incubated aqueous fraction and Vortexing the solution. Again, the aque with Ineurokinin A (final concentration of 1.0 uM) in the ous and organic fractions were each separately removed. The presence of control (neurokinin A) or each of the isolates). organic fractions from the two isolations were combined and The reactions were carried out in 20 mM HEPES (pH 7.4) the aqueous fractions from the two isolations were combined. containing 0.02% bovine serum albumin and 1 mM MnCl The aqueous and organic fractions were dried down and for 4 hours at 25°C. The reaction was then terminated by weighed. The aqueous fraction weighed 116.4 mg and the rapid vacuum filtration onto glass fiber filters. Radioactivity organic fraction weighed 1.3 mg. The organic fraction was trapped onto the filters was measured and compared to control reconstituted in 1.3 mL of 10% methanol in water (for a values in order to ascertain any interactions of the isolates concentration of 0.1 mg/mL), labeled as sample 085426-8 with the neurokinin Abinding site of the NK receptor (mea (Fraction X Isolate) and used in the binding studies. A control Sured as a percentage of specific binding). for sample Fraction X was also made. This control consisted 0331 Sample #19 was prepared by weighing out 103 mg of 10% methanol in water, and was labeled as sample of the contents of a Formulation A capsule. Water (10.3 mL) 085426-9 (note this was the same control as used for sample was added and the solution was Vortexed for one minute. #20) in the receptor binding studies. Thirty mL of ethyl acetate was then added to the solution and 0334 Sample #2 was prepared as follows. A portion (1.8 the Solution was Vortexed again for 1 minute. The sample was mg) of the contents of a Formulation A capsule was weighed then centrifuged using a bench top Beckman centrifuge. out. Forty percent PEG in water plus 0.25% Tween 80 (3.6 Three fractions were formed as a result. The top (organic) and mL) was then added (for a concentration of 0.5 mg/mL) and bottom (aqueous) fractions were collected separately and the the sample was Vortexed. This preparation was labeled as middle fraction was discarded. The top and bottom fractions sample 085426-1 (Sample #2 Isolate) and was tested in the US 2012/O 190743 A1 Jul. 26, 2012 26 receptor binding studies. A control for sample #2 was also were eluted by applying a multi-step gradient of acetonitrile made. This control consisted of 40% PEG in water plus from 20%, 50% to 70%. (Optima R. LC/MS grade, Fisher 0.25% Tween 80, and was labeled as sample 085426-2 in the Scientific). Aliquots of fractions (each fraction containing receptor binding studies. between 10 and 15 ml of eluate) were again assayed in the 0335 The results (obtained from duplicate samples of human NK receptor radioligand binding assay as described each isolate at maximal concentrations) from the receptor above. FIG. 4 shows the results of the binding studies for binding study are presented in the following table. Fractions 25, 51, 65, 115, 135, 155, 161,171, 185, 191 and

#19 #19 Fraction #20 #20 #20. Fraction Target Top Bottom #19 X Top Bottom X #2 #2 Receptor Isolate Isolate Control Isolate Isolate Isolate Control Isolate Control

Neurokinin 2 18% 13% 12% 55% 53% 18% 190 102%. 102%

Bolded data indicate more than 50% inhibition at the concentration tested.

0336. The Fraction X Isolate inhibited neurokinin Abind control (which contained only eluent (0.05% Methanol). ing to its NK receptor by 55%, and Sample #20 Top Isolate Fractions 171 and 185 showed 99.8% and 100.8% binding inhibited neurokinin A binding to its NK receptor by 53%. inhibition of radio-labeled NKA, respectively. Solvent was 0337 To further confirm that binding to and activation of removed and dried samples fractions were stored at -20°C. the NK receptor is antagonized by Sample #20 Top Isolate, prepared as described above, dose response studies were con 0341 The purity of the most active fractions, from 171 ducted. Inhibition of binding of the NK receptor was evalu (99.8% against NK) and 185 (100.8% against NK) was ated in the presence of the following concentrations of #20 identified using HPLC-UV, using standard conditions known Top Isolate (based on the amount of Formulation. A contained to those skilled in the art. The results of these experiments are in Sample #20 prior to extraction): 0.1, 0.3, 1.0, 3.0, 10, 30, shown in FIGS. 5 to 8. FIG. 5 shows a chromatogram of 100 and 300 ug/mL. Fraction 171, and FIG. 6 shows a chromatogram shows a 0338 FIG.3 shows the results of the assay performed with chromatogram of Fraction 185, both fractions being detected the NK receptor. Sample #20 Top Isolate inhibited the ability using 210 nm of light. FIG. 7 shows a chromatogram of of neurokinin A to bind the NK receptor in a concentration Fraction 171, and FIG. 8 shows a chromatogram of Fraction dependent manner, with higher concentrations of Sample #20 185, both fractions being detected using 190 nm of light. Top Isolate providing more binding inhibition and lower con (0342. A 600 MHz H NMR (Bruker) was used to further centrations providing less binding inhibition. The ICso of assess Fractions 171 and 185. These experiments showed that neurokininA was determined to be 6.84x10'ug/mL and the both fractions were pure and that both fractions contained the K, was determined to be 5.76x10' M. The ICs of Sample same compound. Fractions 170, 171, 172,173 and 174 were #20 Top Isolate was determined to be 4.15x10°ug/mL and the combined into a single sample and assayed using the 600 K, was determined to be 3.49x10 M. MHz H NMR HR-mass spectrometry in order to determine the identity of the structure of the compound in the sample Example 6 (i.e., the compound that binds the NK receptor). 0339. The compound that interacts with the NK receptor 0343. The one-dimensional NMR spectroscopy analysis was isolated as follows. A crude extract (1.91 g, off-white shows typical H— and 'C resonance which accounts for a amorphous) of Formulation A suspended in water (HPLC total of 14 (out of eventual 36) protons and 18 carbons. The Grade, J.T. Baker) was loaded into a WPC18 column (40 um, NMR assignment areas following for the protons 4.23 (1H, J. T. Baker). The packed column was eluted with sequential dd, 11.74, 4.70), 4.17 (1H, dd, 11.74, 5.87), 3.95 (1H, m), rounds of water, 30% methanol, 85% methanol and 100% 3.72 (1H, dd, 11.44, 4.11), 3.62 (1H, dd, 11.44, 5.87), 2.37 methanol (HPLC solvent, J. T. Baker). Aliquots of these (2H, dd, 8.78, 7.62), 1.65 (2H, m), 1.35-1.25 (overlapped), methanol containing fractions were then assayed in the 1.13 (1H, m), 0.88 (3H, overlapped) and 0.86 (3H, over human NK receptor radioligand binding assay as described lapped); for 'C-174.1 (C=O), 70.2 (OCH), 65.1 (OCH), above. The results of this assay showed that the greatest 63.2 (OCH), 36.5 (CH), 34.3 (CH), 34.0 (CH), 29.9 (CH), inhibition of binding was present in the fractions eluted with 85% methanol and 100% methanol. These two fractions each 29.5 (CH), 29.5 (CH), 29.4 (CH), 29.3 (CH), 29.1 (CH), exhibited 98.2% activity against N when used at a concen 29.0 (CH), 27.0 (CH), 24.8 (CH), 19.1 (CH) and 11.3 tration of 0.1 mg/ml. Methanol from methanol containing (CH). The CH and CH assignments were confirmed using active fractions (i.e., the fractions eluted with 85% and 100% Distortionless Enhancement by Polarization Transfer methanol) was removed under vacuum and the remaining (DEPT) NMR techniques. The DEPT-90 (middle) and -135 water was removed with lyophilization (Labconco). The (top) experiments further confirmed that there are two CHS dried fractions were stored at -20°C. and 2CHs. Any positive peaks in DEPT-135 which don't 0340. The 0.599 g active fraction (which was a combina appear in DEPT-90 are CHs. tion of the dried fractions eluted with 85% and 100% metha 0344) Multidimensional NMR spectroscopy techniques nol), which showed 98.2% activity against the human NK were used to establish the atomic and functional groups con receptor at 0.1 mg/ml, was applied to a WP C18 column nectivity, which lead to the final 2-dimensional structure elu (d2.1 x50 cm, 40 um, J. T. Baker). The active components cidation. US 2012/O 190743 A1 Jul. 26, 2012 27

0345 These studies thus showed that the active compound 0353 Briefly, the NK receptor agonist assay was per that binds to the NK receptor has the chemical structure formed as follows. Chinese Hampster Ovary-K1 (CHO K1) depicted by Formula (I), the stereochemistry of the chiral cells stably expressing recombinant human NK receptor centers of the isolated compound being unassigned. were plated on mixed extracellular matrix overnight in com 0346 First, the heteronuclear single-quantum correlation (HSQC, H-C) further confirmed the assignment of the units of plete media. One hour before the assay, the media was CH, CH and CH from the one-dimensional experiment. replaced with Hank's Buffered Salt Solution (HBSS) contain (0347 Double-quantum filtered (DQFCOSY) and total ing 0.1% bovine serum albumin. The cells were then loaded correlation (TOCSY or Homonuclear Hartmann Hahn, with dye that measures intracellular calcium and baseline HOHAHA) experiments established the back-bone connec measurements of intracellular calcium were taken. Control tivities of the glyceride unit. The DQFCOSY measures the (agonist (bAla-NKA (4-10) at concentrations ranging from connectivities of adjacent protons, whereas the TOSCY may 1x10' M to 3x107 M) or compound (myristic acid 2,3- reach through several bonds. dihydroxypropyl ester (compound 2) or 6-methyl-myristic 0348. The longer range connectivities (beyond glyceride) acid 2,3-dihydroxypropyl ester (compound 3), each at con were establish using heteronuclear correlation techniques, centrations ranging from 3x107M to 1x10" M), were then namely, HMBC (heteronuclear multiple-bond correlation). added to the appropriate wells of cells. Fluorescence at 485 This method allowed for the connection of the glycerol (C1 nm excitation/515 nm emission was measured every 2 sec H) to the myristic carbonyl through the carboxyl (ester) link onds for at least two minutes. The peak height of fluorescence ages. It also provided the linkage between the C-alpha and in each of the wells receiving compound 2 or compound 3 was -beta protons with the carbonyl of the carboxyl functionality. recorded and compared to the peak height of fluorescence in Connectivity of the C-alpha and -beta protons could also be the wells receiving the control. The results of this assay are extended to include Some the CH groups of the myristic acid presented in FIG. 11, which is a graph of the percent maxi adjacent to them. 0349. At the conclusion of the NMR analysis, the com mum value for the Ib Ala-NKA (4-10) control (% Maximum pound that bound the NK receptor was identified as the Response) versus the concentration of compound for the con compound of Formula (I). This assignment resulted in the trol, myristic acid 2,3-dihydroxypropyl ester (cmpd #2) or proposed molecular formula as CHO with the corre 6-methyl-myristic acid 2,3-dihydroxypropyl ester (cmpd #3) sponding molecular weigh of approx. 316, which was then (log(compound) (M)). confirmed by AccuTOF experiments. 0354. The NK receptor antagonist assay was performed essentially as follows. CHO-K1 cells stably expressing Example 7 recombinant human NK receptor were plated on mixed extracellular matrix overnight in complete media. One hour 0350 6-methyl-myristic acid 2,3-dihydroxypropyl ester before the assay, the media was replaced with Hank's Buff was synthesized as described above, and myristic acid 2.3- ered Salt Solution (HBSS) containing 0.1% bovine serum dihydroxypropyl ester was obtained, and the compounds dis albumin. The cells were then loaded with dye that measures solved in dimethylsulfoxide (DMSO). The effects of various intracellular calcium and baseline measurements of intracel concentrations of 6-methyl-myristic acid 2,3-dihydroxypro lular calcium were taken. Controls (antagonist GR 159897 at pyl ester and myristic acid 2,3-dihydroxypropyl ester on the concentrations ranging from 3x10 M to 1x10 M or human NK receptor binding assay described above in bAla-NKA (4-10) at concentrations ranging from 1x10' Example 5 were tested. FIG. 9 shows the results of the assay M to 3x107M) (the calcium effects of bala-NKA (4-10) performed with the NK receptor in the presence of 6-methyl dissipate over time, therefore, bAla-NKA (4-10) can act myristic acid 2,3-dihydroxypropyl ester (labeled in FIG. 10 like an antagonist in the antagonist assay, by blocking addi as compound “107236-1'). In general, 6-methyl-myristic tional effects of Ib Ala-NKA (4-10)) or sample (myristic acid 2,3-dihydroxypropyl ester inhibited the ability of neuro acid 2,3-dihydroxypropyl ester (compound 2) or 6-methyl kinin A to bind the NK receptor in a concentration-depen myristic acid 2,3-dihydroxypropyl ester (compound 3), each dent manner. The ICs K, of neurokinin A and 6-methyl at concentrations ranging from 3x107M to 1x10'M, were myristic acid 2,3-dihydroxypropyl ester are shown in FIG.9. then added to the appropriate wells of cells. After ten minutes, 0351 FIG. 10 shows the results of the radioligand binding agonist b Ala-NKA (4-10) (0.3 nM final concentration) was assay performed with the NK receptor in the presence of added. Fluorescence at 485 nm excitation/515 nm emission myristic acid 2,3-dihydroxypropyl ester (labeled in FIG. 10 was measured every 2 seconds for at least two minutes. The as compound “107236-2). Myristic acid 2,3-dihydroxypro peak height of fluorescence in each of the wells receiving pyl ester also inhibited the ability of neurokinin A to bind the controls, compound 2 or compound 3 was recorded and com NK receptor. The ICso K, of neurokinin A and myristic acid pared to the peak height of fluorescence in the wells receiving 2,3-dihydroxypropyl ester are shown in FIG. 10. only the agonist. The results of this assay are presented in FIG. 12, which is a graph of the percent maximum value for Example 8 the bala-NKA (4-10) control (% Maximum Response) 0352 6-methyl-myristic acid 2,3-dihydroxypropyl ester Versus the concentration of compound for the controls, myris was synthesized as described above, and myristic acid 2.3- tic acid 2,3-dihydroxypropyl ester (cmpd #2) or 6-methyl dihydroxypropyl ester was obtained. They were each pre myristic acid 2,3-dihydroxypropyl ester (cmpdfi3) (log(com pared as solutions by addition of dimethylsulfoxide (DMSO) pound) (M)). As shown in FIG. 12, each of myristic acid to a concentration of 10 mM. These compounds were then 2,3-dihydroxypropyl ester and 6-methyl-myristic acid 2.3- used in cellular/functional calcium flux agonist and antago dihydroxypropyl ester displayed antagonist activity in this nist assays to determine the effect the compounds have on functional NK receptor antagonist assay. human NK receptor activity as measured by changes intra 0355. It is believed that the preparation and use of com cellular calcium measurements. These assays were carried pounds of the present invention, including individual com out based on the method of Gerard et al. pounds encompassed by Formula 1, will be apparent from the US 2012/O 190743 A1 Jul. 26, 2012 28 foregoing description of exemplary embodiments, and may 0369. Khawaja AM, Rogers D F. Tachykinins receptor to thus be claimed as such. It will be obvious to a person of effector. Int J Biochem Cell Biol. 1996; 28(7): 721-738. ordinary skill in the art that various changes and modifica 0370 Kendler KS, Walters E. E. 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Pharmacol. 1993 Dec. 21; 250(3):R11-2. US 2012/O 190743 A1 Jul. 26, 2012 29

0384 Teixeira RM, Santos AR, Ribeiro SJ, Calixto JB, wherein, optionally, there is a second double bond Rae GA, De Lima TC, Effects of central administration of formed between adjacent methylene groups of for tachykinin receptoragonists and antagonists on plus-maZe mula (1) wherein each carbon thereof is bonded to at behavior in mice. Eur J. Pharmacol. 1996 Sep. 5; 311(1): least one hydrogen; 7-14. or X is —(CH2) , 0385 Toulouse M. Coelho A, Fioramonti J. Lecci A, Z is Maggi C, Bueno L. Role of tachykinin NK receptors in normal and altered rectal sensitivity in rats. Br J Pharma cology 2000 129, 193-199. (CH2)(CH3, A 0386 Treatment of Chronic Depression (Editorial), FCC NEJM 342:1518-1520, 2000. v (0387 Walsh DM, Stratton SC, Harvey FJ, Beresford IJ, H Hagan RM, The anxiolytic-like activity of GR159897, a non-peptide NK receptor antagonist, in rodent and pri mate models of anxiety. Psychopharmacology (Berl). 1995 September: 121(2):186-91. Y is absent, and C and C, togetherform a double bond, 0388 Ware J E Jr. Sherbourne CD, The MOS 36-item R is —(CH), CH or is —H. short-form health survey (SF-36). 1. Conceptual frame t and u are integers, work and item selection Medical Care 1992, 30:473-483. t=1 to 5, 1-76. (canceled) u=0 to 12, 77. A compound having the following the structure: 5st+us 13 for all tandu, and wherein, optionally, there is a second double bond formed between adjacent methylene groups of for (1) mula (1) wherein each carbon thereof is bonded to at W least one hydrogen, B X Z including or a pharmaceutically acceptable salt of the com V n1n| pound. 78. The compound of claim 77, wherein A and B are both R - OH. A 79. The compound of claim 77, wherein V and Ware both OXygen. wherein: 80. The compound of claim 77, wherein R is —(CH) A and B are independently —OH or —SH, CHs. V and W are independently oxygen or sulfur and at least 81. The compound of claim 77, wherein p is 0 to 2. one of V and W is oxygen, 82. The compound of claim 77, wherein p is 0 or 1. R is -(CH2)CH or is -H, and 83. The compound of claim 77, wherein p is 0. p is an integer from 0 to 3, and: 84. The compound of claim 77, wherein n=2 to 12 and X is —(CH), , 7sm-ins 13. Y is H, 85. The compound of claim 77, wherein n=3 to 11 and 8sm+ns 12. Z is —(CH), , 86. The compound of claim 77, wherein n=4 to 10 and m and n are integers, 9sm-ins 11. m=1 to 5, 87. The compound of claim 77, wherein n=5 to 9 and n=4 to 14, m+n=10. 6sm+ns 14 for all m and n, and 88. The compound of claim 77, wherein m=2 to 4. wherein, optionally, there are up to two carbon-carbon 89. The compound of claim 77, wherein m-3. double bonds, each double bond formed between 90. The compound of claim 77, wherein r=2 to 12 and adjacent methylene groups of formula (1) wherein, if 6sq+rs 12. there are two said double bonds each carbon thereof is 91. The compound of claim 77, wherein r–3 to 11 and bonded to at least one hydrogen; 7sq+rs 11. or X is 92. The compound of claim 77, wherein r-4 to 10 and 8sq+rs 10. 93. The compound of claim 77, whereinr-5 to 9 and q+r=9. V 94. The compound of claim 77, wherein q1 to 3. CRF / 95. The compound of claim 77, wherein q2. -(CH2) 96. The compound of claim 77, wherein u=1 to 11 and 6st+us 12. 97. The compound of claim 77, wherein u=2 to 10 and Y is absent, and C and C togetherform a double bond, 7 stus 11. Z is —(CH), , 98. The compound of claim 77, wherein u=3 to 9 and q and rare integers, 8stus 10. q=0 to 4, 99. The compound of claim 77, wherein u=4 to 8 and r=1 to 13, t-u=9. 5sq+rs 13 for all q and 4, and 100. The compound of claim 77, wherein t=2 to 4. US 2012/O 190743 A1 Jul. 26, 2012 30

101. The compound of claim 77, wherein t—3. 110. A substantially stereochemically pure compound of 102. The compound of claim 77, wherein if said up to two claim 77 having the formula: carbon-carbon double bonds are present, then each said bond is formed between methylene groups of Z. 103. The compound of claim 102, wherein said up to two carbon-carbon double bonds is a one said bond. 104. The compound of claim 77, wherein if said second double bond is present, then said bond is formed between HO methylene groups of Z. 105. The compound of claim 77, wherein said up to two 111. A pharmaceutical composition comprising the com carbon-carbon double bonds and said second double bond are pound of claim 77 and a pharmaceutically acceptable carrier. absent. 112. A dosage form comprising the compound of claim 77. 113. A method for treating a disorder or disease associated 106. A compound of claim 77 having the following for with neurokinin 2 (NK) receptor activity, said method com mula: prising the step of administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, of claim 77 to a subject in need thereof. 114. The method of claim 77, in which A and B are each —OH, V and W are oxygen, R is H. X is —(CH), , Z is HO 1. —(CH), , m is 3., n is 7, and the compound contains no O (CH2)6 C=C double bonds, to a subject in need thereof. 115. The method of claim 114, wherein said disorder or HO disease associated with said NK receptor activity is a depres sive mood disorder, anxiety disorder, irritable bowel syn drome, inflammatory bowel disease, inflammatory airway 107. A substantially stereochemically pure compound of disease or urinary incontinence. claim 77 having the formula: 116. The method of claim 113, wherein the compound is contained in a pharmaceutical formulation comprising a pharmaceutically acceptable carrier. 117. A method for treating a disorder or syndrome associ ated with a depressive mood disorder, said method compris ing the step of administering a therapeutically effective amount of the compound, orpharmaceutically acceptable salt thereof, of claim 77 to a subject in need thereof. 118. The method of claim 117, in which A and B are each —OH, V and W are oxygen, R is H. X is —(CH), , Z is 108. A substantially stereochemically pure compound of —(CH), , m is 3., n is 7, and the compound contains no C=C double bonds, to a subject in need thereof. claim 77 having the formula: 119. The method of claim 117, wherein the disorder or syndrome is a disorder of the brain or nervous system, anxiety disorder, sexual dysfunction, Substance abuse, eating disor der or hormone disorder.

120. A method of treating a disorder or condition treatable by an antidepressant, said method comprising the step of administering a therapeutically effective amount of the com Hd I pound, or pharmaceutically acceptable Salt thereof, of claim HO 77 to a subject in need thereof. 121. The method of claim 120, in which A and B are each 109. A substantially stereochemically pure compound of —OH, V and Ware oxygen, R is H. X is —(CH), , Z is —(CH), , m is 3., n is 7, and the compound contains no claim 77 having the formula: C=C double bonds, to a subject in need thereof. 122. A method for modulating an activity of an NK recep tor comprising contacting the NK receptor with an effective amount of the compound, or a pharmaceutically acceptable salt thereof, of claim 77. 123. The method of claim 122, in which A and B are each —OH, V and Ware oxygen, R is H. X is —(CH), , Z is —(CH), , m is 3., n is 7, and the compound contains no C—C double bonds.